Pindolol, a β-adrenergic and presynaptic 5-HT1A antagonist, when added to specific serotonin reuptake inhibitors, potentiates the antidepressant action, leading to an earlier onset of effect. Following on from the suggestion that nefazodone, a specific serotonin reuptake inhibitor and antagonist of 5-HT2, improves 5-HT1A-mediated transmission, we used a pindolol and nefazodone combination treatment for major depressive disorder. Twenty outpatients underwent a 4-week trial. Patients were seen twice a week, and completed efficacy and safety measures including the 17-item Hamilton Depression Scale, the Montgomery-Asberg Depression Rating Scale and the Clinical Global Impression scales. Results demonstrated significant improvement in all efficacy measures after one visit (2–4 days of treatment), with decreasing depression scores on all measures continuing throughout the trial. After 1 week of treatment, 15 out of 20 patients had experienced a 50% or greater reduction in their 17-item Hamilton Depression Scale scores. Remission rates were dramatic, with 40% of patients in remission after 1 week of treatment and 90% after 4 weeks. This open study of nefazodone-pindolol combination therapy suggests that this may be a new treatment option for patients with major depressive disorder; however, it needs to be replicated in a double-blind trial before conclusions regarding efficacy and safety can be made.