The aim of this study was to compare the efficacy and tolerability of reboxetine, a uniquely selective noradrenaline reuptake inhibitor, with the selective serotonin reuptake inhibitor, fluoxetine. A double-blind, randomized, parallel-group, multicentre design was employed. One hundred and sixty-eight patients with acute major depressive episodes were randomized to receive oral reboxetine (8-10 mg/day) or oral fluoxetine (20-40 mg/day). The treatment period was 8 weeks. Reboxetine and fluoxetine were similarly effective as assessed by the mean reduction in total Hamilton Depression Rating Scale score, the percentage of responders and patients in remission, Clinical Global Impression severity of illness and global improvement scores and Montgomery-Asberg Depression Rating Scale. A sub-analysis of patients with severe depression indicated that reboxetine had superior efficacy compared with fluoxetine. Both treatments resulted in some improvement in Social Adaptation Self-evaluation Scale total scores and this was more evident for those patients treated with reboxetine who achieved remission. Both treatments were well tolerated. The results indicate that reboxetine is an effective and well tolerated antidepressant, being more effective than fluoxetine in patients with severe depression, and more effective in terms of social functioning in those patients who achieved remission.