This randomized, double-blind, parallel-group design study of 100 outpatients with major depressive disorder is the first study in the United States to compare the efficacy and tolerability of fluvoxamine (100-150 mg/day) and fluoxetine (20-80 mg/day). After a variable, single-blind, washout period, patients were randomized to receive either fluvoxamine (51 patients) of fluoxetine (49 patients) for 7 weeks. Efficacy was assessed with the 21-item Hamilton Rating Scale for Depression (HAM-D), and Clinical Global Impressions scale for severity and improvement. Eighty-four percent of each treatment group completed the study with each group having a mean score at end point of less than 10. Both groups demonstrated a 60% improvement in HAM-D scores over the 7-week trial. There were no statistically significant differences observed between the two groups on any efficacy parameter. The medications were well tolerated, with only two patients in each group who were terminated because of side effects. There were differences in the side-effect profiles, with fluvoxamine being associated with less nausea than fluoxetine. In summary, fluvoxamine and fluoxetine were equally effective in reducing depressive symptoms, but the two drugs displayed slightly different side-effect profiles.