Objective: To investigate the role of a patent foramen ovale in the pathogenesis of multiple brain lesions acquired by sport divers in the absence of reported decompression symptoms. Design: Prospective double blind cohort study. Setting: Diving clubs around Heidelberg and departments of neuroradiology and neurology. Subjects: 87 sport divers with a minimum of 160 scuba dives (dives with self contained underwater breathing apparatus). Main outcome measures: Presence of multiple brain lesions visualised by cranial magnetic resonance imaging and presence and size of patent foramen ovale as documented by echocontrast transcranial Doppler ultrasonography. Results: 25 subjects were found to have a right-to-left shunt, 13 with a patent foramen ovale of high haemodynamic relevance. A total of 41 brain lesions were detected in 11 divers. There were seven brain lesions in seven divers without a right-to-left shunt and 34 lesions in four divers with a right-to-left shunt. Multiple brain lesions occurred exclusively in three divers with a large patent foramen ovale (P = 0.004). Conclusions: Multiple brain lesions in sport divers were associated with presence of a large patent foramen ovale. This association suggests paradoxical gas embolism as the pathological mechanism. A patent foramen ovale of high haemodynamic relevance seems to be an important risk factor for developing multiple brain lesions in sport divers.