INTRODUCTION: Erectile dysfunction (ED) and depression are highly prevalent medical disorders affecting men of diverse cultures throughout the world. Tianeptine is a new antidepressant drug with less adverse effects on sexual functions. AIM: To evaluate the efficacy of tianeptine in the treatment of mild to moderate depression with ED. METHODS AND MAIN OUTCOME MEASURES: A randomized, double-blind, placebo-controlled, crossover trial. Subjects were assigned either tianeptine or matching placebo, each for 8 weeks. All patients were followed up on monthly basis where they were asked to complete three assessment questionnaires, namely, Anxiety and Depression Scale, Brief Sexual Inventory, and Quality-of-life and erection questionnaire. All patients were asked a global assessment question. Treatment-responsive subjects were defined as study participants who had scores 1-16 on the Anxiety and depression Scale, showed normal erectile function on the Brief Sexual Inventory, and answered "yes" to the global assessment question. RESULTS: Of the 237 consecutive men complaining of ED of >6 months and screened for this study, 110 patients met our inclusive criteria; 42 declined to participate. The remaining 68 patients were randomly assigned to treatment. Significant improvement (P < 0.05) was observed during the active drug phase in all three assessments questionnaires, in comparison with the placebo phase. Forty-eight patients (72.7%) of the subjects during the active drug phase were classified as responders, while 19 (27.9%) of the subjects during placebo phase were classified as responders. CONCLUSIONS: Tianeptine could be considered an effective therapy for the treatment of depression and ED. Further large-scale multicentered studies are warranted.