We compared the antidepressant efficacy and patient tolerance of two different doses of milnacipran (75 mg and 150 mg daily) in 66 outpatients with major depression, using the 17-item Hamilton Depression Rating Scale (HDRS). Only new patients who had never experienced frank depressive episodes before, or those who had remained free from thymoregulators for more than 1 year without recurrence of depressive symptoms, were recruited. Subjects were randomly selected to receive a daily dose of milnacipran that reached either 75 mg or 150 mg within 2-3 weeks and then remained stable over an 8-week period. The results showed a significant superiority of milnacipran at 150 mg/day over 75 mg/day at the end of the study period in both response (50% or more decrease in total score from baseline, P=0.026) and remission (total HDRS score lower than 7 points, P=0.034). A response was recorded for 56.0% of the patients treated with 75 mg of milnacipran and for 84.6% of those treated with 150 mg after the 8-week study period. No significant difference was seen between the treatment groups for either individual or total incidence of adverse events. Notably, nausea and vomiting occurred most often immediately after the first visit, when subjects in both groups started with a daily dose of 50 mg. We conclude that additional comparisons between different doses of milnacipran should be performed to confirm or deny the linear dose/efficacy relationship observed in the present study.