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Verano de 1954. Los agentes judiciales Teddy Daniels (Leonardo DiCaprio) y Chuck Aule (Mark Ruffalo) son destinados a una remota isla del puerto de Boston para investigar la desaparición de una peligrosa asesina (Emily Mortimer) recluida en el hospital psiquiátrico Ashecliffe, un centro penitenciario para criminales perturbados dirigido por el siniestro doctor John Cawley (Ben Kingsley). Pronto descubrirán que el centro guarda muchos secretos, y que la isla esconde algo más peligroso que los pacientes...
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