The objective of the study was to compare the efficacy and safety ofmilnacipran and Venlafaxine in major depressive disorder. The study was conducted in 120 patients suffering from major depressive disorder as per DSM-IV criteria. Patients were randomized to two groups and were given milnacipran (25, 50mg BD) and venlafaxine(75, 150mg OD) for 8 weeks. The primary efficacy parameter was the Hamilton Depression Rating Scale (HDRS-17) and Montgomery and Asberg depression rating scale (MADRS). Secondary efficacy parameters included proportion of patient responds to the treatment, proportion of patient remission to the treatment andchanges in the score of clinical global impression (CGI) scale. Safety evaluation was based on treatment emergent adverse effects. There was significant decrease in HDRS, MADRS, CGI scores from baseline to end of treatment(p<0.05) in both the groups. However the difference in scores between two groups was not statistically significant. Total mean HDRS score decreased from 30.54 (SD=5.93) to 11.96 (SD=5.18) in milnacipran group and from 32.54 (SD=8.19) to 11.58 (SD=5.99) in venlafaxine group at the end of treatment. Total mean MADRS score decreased from 37.56 (SD=6.66) to 15.41 (SD=5.78) in milnacipran group and from 38.98(SD=9.42) to 14.77 (SD=6.57) in venlafaxine group at the end of treatment. Responder and remission rate was 72.22% and 31.48% in milnacipran group as compared to 75.00% and 30.77% in venlafaxine group respectively. There was no significant difference in adverse effectsbetween two groups. The findings of this study indicate that milnacipran may be an effective and safe antidepressant in Indian patients of major depressive disorder. It is equally effective to venlafaxine in patients of depression.