Background: Serotonin (5-HT) neuronal systems have been implicated in the modulation of obsessive-compulsive disorder (OCD) symptoms. 5-HT3 receptor antagonists have been found to act as anxiolytics anxiolyties in selected animal models of anxiety; in particular, those involving an element of risk assessment. Since the compulsions of OCD are frequently triggered by an abnormal perception of risk, a pilot study was initiated to determine whether the 5-HT3 receptor antagonist ondansetron might have efficacy in the treatment of OCD. Method: Eight medication-free subjects with a DSM-IV diagnosis of OCD and a Yale-Brown Obsessive Compulsive Scale (YBOCS) score ≥ 16 entered an 8-week open-label trial of ondansetron at a fixed dose of 1 mg 3 times daily in a study conducted between February and October 1998. Results: Six subjects completed the trial. Three subjects (37%) achieved a clinically significant response (≥ 35% reduction in YBOCS score). For these subjects, the average reduction in YBOCS-rated symptoms was 55%. In aggregate, the 8 patients exhibited a 28% reduction in YBOCS-rated symptoms over the course of the trial. The medication was well tolerated. Conclusion: These results suggest that low-dose ondansetron may have promise as a monotherapy for some patients suffering from OCD.