Serotonergic drugs such as pergolide have been associated with the development of cardiac valvular myxoid thickening and regurgitation in humans and more recently in rats. These effects are potentially mediated by the 5-hydroxytryptamine (2B) receptor (5-HT(2B)R). Therefore we sought to determine whether cyproheptadine, a 5-HT(2B)R antagonist, might prevent toxic valvulopathy in an animal model of pergolide-induced valvular heart disease. For this purpose, fifty male Wistar rats received daily intraperitoneal injections of pergolide 0.5 mg/kg (n=14), pergolide 0.5 mg/kg combined with cyproheptadine 10 mg/kg (n=12), cyproheptadine 10 mg/kg (n=12) or no injections (control, n=12) for 20 weeks. Echocardiography was performed blindly at baseline, 10 and 20 weeks followed by pathology. At baseline, no differences between groups were found with echocardiography. At 20 weeks, aortic regurgitation was present in all pergolide animals while it was less frequently observed in the other groups (P<0.0001). For the other valves this difference was less pronounced. On histopathology, not only aortic but also mitral valves were thicker, myxoid and exhibited more 5-HT2BR-positive cells in the pergolide animals compared to the other groups. Moreover, regurgitant aortic and mitral valves were thicker than non-regurgitant aortic and mitral valves. In conclusion, we found that cyproheptadine prevented pergolide-induced valvulopathy in rats which was associated with a reduced number of 5-HT2BR-positive valvular cells. This may have important clinical implications for the prevention of serotonergic drug-induced valvular heart disease.