Summary Background Major depression affects more than 5% of the population and is a serious health and economic problem. Antidepressants have a slow onset of action and are effective in less than two-thirds of patients. The biochemical effects of selective serotonin reuptake inhibitors may be limited by the negative feedback from serotonin autoreceptors. Pindolol is an antagonist of both serotonin autoreceptors and β-adrenoceptors. We studied the effect of the addition of pindolol to fluoxetine antidepressant treatment. Methods Of 132 eligible patients with major depression, 111 were randomly assigned to treatment with fluoxetine (20 mg daily) and either placebo or pindolol (7·5 mg daily). Patients were assessed twice a week for the first 3 weeks of active treatment and then once a week until the end of the study (42 days). Hamilton and Montgomery-Asberg depressionrating scales were used to assess depression severity. Finding The proportion of patients who responded to treatment with fluoxetine and pindolol was greater than that with fluoxetine and placebo (41/55 [75%] vs 33/56 [59%], [90% CI 1·1–30·1], p=0·04). The proportion of patients who achieved a sustained response was also greater in the fluoxetine and pindolol group than in the fluoxetine and placebo group (38/55 [69%] vs 27/56 [48%] [5·9–35·9], p=0·03). The number of days to reach a sustained response was lower in the fluoxetine and pindolol group than in the fluoxetine and placebo group (median 19 vs 29 days, p=0·01), however, there was no difference in the time-toonset of clinical improvement when stringent conditions were used (15 vs 18 days, p=0·20). Interpretation The addition of pindolol to fluoxetine antidepressant treatment increases the effectiveness of fluoxetine therapy. Further work is needed to resolve whether the time to clinical improvement benefits from this combination and whether the increase in efficacy occurs with other antidepressants.