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Vid universitetssjukhuset Princeton Plainsboro i New Jersey hanterar geniet doktor Gregory House diverse hälsomysterium i riktigt Sherlock Holmes-stil, samtidigt som han spelar spel med sina kollegor som bl.a. inkluderar hans bästa vän onkologen James Wilson. House, som är en kärv specialist inom infektionssjukdomar, löser problemen med hjälp av sitt team av unga diagnostiker, och trots sin brutala ärlighet och antisociala tendenser gör hans felfria instinkter och okonventionella tänkande att House får stor respekt från sina medarbetare.
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