We aimed to evaluate the safety and efficacy of venlafaxine and sertraline in patients with depression in Parkinson's disease (PD). The patients were assigned randomly and consecutively to treatment with sertraline or venlafaxine in a double blind trial for 8 weeks. Clinical efficacy was assessed after 4(th) and 8(th) weeks of treatment by using Hamilton Depression Rating Scale (HAM-D) and Montgomery-Asberg Depression Rating Scale (MADRS). Antiparkinsonian drugs and other medications were unchanged throughout the study. Patients with motor ossilations, those with clinically relevant cognitive dysfunction on neurological examination and those receiving antidepressant medications in the last 3 months were excluded in this study. Mean HAM-D and MADRS scores decreased significantly in both groups at the end of the 8 weeks of treatment. Some cholinergic side effects of both drugs were not serious, and none of the patients experienced serotonin syndrome. Venlafaxine and sertraline appear to be equally effective in the treatment of major depression in PD.