Our research group has conducted clinical trials of standard (imipramine, fluoxetine, and sertraline) and alternative antidepressants (dextroamphetamine and testosterone replacement therapy) in the treatment of clinical depression among patients with human immunodeficiency virus (HIV) illness. This report presents secondary analyses of data pooled from these trials with the purpose of comparing the antidepressant efficacy of these various agents. In all trials, a DSM-III-R depressive disorder was the primary criterion for study entry, and each treatment resulted in significant improvement after both 2 and 6 weeks of treatment according to the Hamilton Depression Rating Scale (HDRS). Response rates for standard antidepressants ranged from 70% to 74%, with similar, high response rates found in trials of dextroamphetamine (93%) and testosterone (81%). The response rate of each active drug treatment was superior to that of placebo (33%). Each treatment was well-tolerated in terms of side effects, and there was essentially no effect of any treatment on CD4 cell count. Differences in trial design, entrance criteria, and measurements require that caution be used in interpreting these results; nonetheless, each of the five treatments studied demonstrated strong efficacy and possessed relatively unique benefits, providing health care providers with valuable treatment options in addressing individual needs of patients.