The movie starts off with a house, as homeowner Meg (Cheryl Hines) shows Henry Poole (Luke Wilson) a house he is looking at. He asks how much this house cost ($350,000) and inquires about the house across the street. Meg says that the buyers won't sell that house and are really happy. Henry says he'll take the house, but Meg tells him that she can maybe knock the value off because the house isn't properly ready. Henry says he'll pay the asking price. Henry later goes to the supermarket and buys some alcohol and has it rung up from a checkout girl (Rachel Seifereth), he notices her name tag: Patience.
Henry is getting situated in his new house when his neighbor Esperanza (Adriana Barraza) rings the doorbell and gives him some food. Esperanza says the man who was living there recently died, and she came over and found him by the kitchen sink. Henry thanks her and leaves. Meg comes back the next day to check up on how he is doing. He didn't want the house to be touched, and complains about the growing of the grass. He then states he isn't going to be living there that long anyway, and Meg is puzzled as she leaves.
Shortly after that, Henry hears the same conversation he had with Meg earlier. He wonders where the sound is coming from, and discovers it is coming from next door: a six-year old girl named Millie (Morgan Lily). When he attempts to speak to her, she runs off. Henry then takes a little nap and when he wakes off, he discovers Esperanza praying to a wall. Henry goes over and talks to Esperanza, who is on the phone with somebody. He asks Esperanza who she was praying to and she shows him the face of Christ on the wall. Henry says it’s unclear and looks like a water stain, and wants to know who she was talking to on the phone. The doorbell rings and Father Ramón Salazar (George Lopez) comes to check it out. He says he can see where it might be interpreted as a face, but states that it may just be water stain. Henry forces them both off his property, which gets Esperanza mad.
Henry later sees Millie out there praying and looking at the wall, and Henry goes to ask what she's doing. Millie gets frightened by him and runs off, leaving her tape recorder behind. The previous conversation is taped as well. He returns the tape recorder back to Mille's mother Dawn (Radha Mitchell). Later that day, Henry goes on errands and returns home to find Esperanza sneaking three old ladies back to see "the face". He goes to his backyard and sees they've put a bottle with some flowers and red paint on his wall. He returns it to Esperanza, and berates the old ladies. He then shows Esperanza the red paint he found on his wall, and Esperanza states that it is not paint, but blood. Henry insists they leave the premises now, and tries to wash the 'face of Christ" himself, however it does not seem to come off.
The film flashbacks to six months earlier, where we see a nurse trying unsuccessfully to obtain a blood sample from Henry (she keeps missing his veins three or four times). She finally gets it, and then he sees the doctor about his condition. The movie goes back to a blurry vision of a supermarket, and we see that it is Patience. Patience puts her glasses on, clearing the blurred vision. She immediately recognizes Harry and motions him over to her counter. Henry notices that he is not buying booze, but cleaning supplies, and tries to talk to him to see if he's sad or depressed. Henry doesn't want to talk about it, and gets to the point where he gets mad. Patience retracts but later apologizes.
Henry is next seen scrubbing the wall down of the stain, but to no avail. Dawn talks to him through the gate, Henry then goes inside to unclog the kitchen sink and fins a box inside. It contains a picture of Esperanza and possibly the previous house owner. Henry notices her working on his flower bush making chit-chat with Josie (Beth Grant) about having the church come to Henry's house to test the blood. Henry objects, but instead shows her the picture. Esperanza begins crying, as she goes to Henry's kitchen and looks at the pictures. She tells him that the man who previously lived there was her boyfriend (forgot his name), and that she was the love of his life. She was devastated when he died, as true love comes along once. Henry, feeling a sense of remorse, decides to let Esperanza bring her church friends over to see the statue. He talks to Father Salazar while a blood sample is taken to be analyzed. The Father is too confused when Henry mentions that he won't be living here long.
After they leave, Henry hears the recorded conversation he had with Ramón. He manages to talk to Millie, who doesn't speak. That night, Dawn comes in to check on Millie but finds she's not in her room. Dawn finds Millie next door, touching the wall. Dawn gets Millie from Henry's house, and Millie finally sound out a word from her mouth. Dawn is surprised, and pulls Millie closer to her, to which Millie says "Mommy". The two embrace as Henry walks out and discovers them. Henry takes both of them in, and Dawn explains that Millie hasn't spoken a word in over a year because of her father leaving, Dawn is now a single mother raisin her daughter on her own.
Henry confronts Esperanza the next day and asks if she put Mille up to it, to which Esperanza takes some responsibility. Henry gets mad and starts mocking her religion and belief, and she walks out before Henry, realizing his mistake, apologizes. She comes by later, and surprises him by taking Henry to his old house: this was the house he had originally wanted to buy and the place that made him happy. He takes a picture of his family and puts it on an empty wall in his house.
Henry is invited by Dawn on a play-date with Millie the next day, where all three get in a water balloon fight. Dawn comes by later and presents him cookies as a way of thanking him. Henry lies down and eats all the cookies that night and takes it back the next day. Henry also asks if he wants to go out to dinner with him, and she says yes without hesitation. Henry then decides to take a walk down to the river, which has become an overpass. At the same time a younger image of himself rides along a bike. Henry ends on an overpass spot, where he wrote the words: "Henry Poole Was Here" as a child. It's still there. Henry arrives home later that night and writes the words under the picture.
The next day he finds Patience at his house, touching the wall. Her blurred vision is cured, and she doesn't need her glasses anymore. Later on he asks Esperanza if they can watch as people line up outside the house to touch 'the face of Christ'. He takes Dawn out for some pizza next door, set up by romantic candlelight Dawn asks where he was yesterday, and he states that he was at a place he used to go during his childhood on the days when his parents fought. Mille wakes up, and Dawn excuses herself to tuck Millie back into bed. She then joins Henry, who is upset with the fact he's going to die soon. Dawn reassures him that all they have is now and kisses him.
The next day, Dawn arrives and tells Henry that there's something wrong with Millie. Millie is unresponsive, and won't move. Henry goes into her room and discovers she recorded their conversation: she now knows she's going to die soon. They rush her to the doctor's office, who insists nothing is wrong with her. Henry goes back home and is shocked to find a huge line of people outside his house. He berates Esperanza and the people about their faith, and takes an axe and destroys the water stain on his wall. After he is done, Esperanza tells him the test results of the bloodstain came back: it was real. The left side of the house comes crumbling down on Harry, who is admitted to the hospital shortly after. Esperanza is at Harry's side when he comes to, and asks him why he didn't tell her about his disease in the first place. Harry wanted to be left alone, and as he tries to leave the hospital, ripping the IV from his hand, he falls over and is presumed dead.
But Henry is woken up by Millie and Dawn, who tell him the good news. The doctors have gone back over his file, and reports that Henry doesn't have the disease. Henry is ecstatic about hearing it, and shortly thereafter arrives back home with some cookies from Dawn and a welcome home card from Millie. Henry passionately kisses Dawn, and the final shot is Henry taking down the family picture and crossing off one of "Was" in "Henry Poole Was Here" and replaces it to now read "Henry Poole Is Here". He now feels good about his newfound appreciation towards life (again).
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