Background: Patent foramen ovale (PFO), male sex, age, and body mass index (BMI) were all identified as potential risk factors of decompression sickness (DCS). It has been debated whether PFO might cause unprovoked DCS (i.e. without violation of decompression procedure) due to paradoxical embolization of venous gas emboli. To date, there are no data on the incidence or risk factors of unprovoked DCS. This study sought to evaluate the risk factors of unprovoked DCS in recreational divers. Methods: A total of 489 consecutive divers were screened for PFO between January 2006 and January 2014 by means of transcranial Doppler. All patients were prospectively included in the study registry. Survival analysis techniques were used to assess for risk factors for unprovoked DCS. Age, sex, BMI, PFO presence, and grade were analyzed. The total sum of dives was used as a measure of time. Results: The group performed a total of 169,411 dives (mean 346 AE 636). Thirty-six (7%) of the divers suffered from an unprovoked DCS. The frequency of PFO was 97.2% in divers with a history of unprovoked DCS and 35.5% in controls (p < 0.001). There was no difference in sex, age, BMI, or total number of dives between the respective groups. In the adjusted Cox proportional hazards model, PFO grade 3 was a major risk factor for unprovoked DCS; there was a slight protective effect of increasing age. Conclusions: We demonstrated that a high-grade PFO was a major risk factor for unprovoked DCS in recreational scuba divers.