Patency of the foramen ovale (PFO) may be a cause of unexplained decompression sickness (DCS) in sports divers. To assess the relationship between PFO and DCS, a case-control study was undertaken in a population of Belgian sports divers. Thirty-seven divers who suffered from neurological DCS were compared with matched control divers who never had DCS. All divers were investigated with transesophageal contrast echocardiography for the presence of PFO. PFO size was semiquantified on the basis of the amount of contrast passage. Divers with DCS with lesions localized in the high cervical spinal cord, cerebellum, inner ear organs, or cerebrum had a significantly higher prevalence of PFO than divers with DCS localizations in the lower spinal cord. For unexplained DCS (DCS without commission of any diving procedural errors), this difference was significant for large PFOs only. We conclude that PFO plays a significant role in the occurrence of unexplained cerebral DCS, but not of spinal DCS. We further stress the importance of standardization and semiquantification of future PFO studies that use transesophageal contrast echocardiography.