Psychological effects of participation in Protocol 019, a zidovudine placebo-controlled clinical trial, were investigated. Forty-six Protocol 019 subjects and 27 control asymptomatic human immunodeficiency virus-seropositive subjects were assessed at entry, 2 months, 6 months, and after trial modification. At baseline there were no psychological differences. Most Protocol 019 and control subjects were depressed on at least one psychological measure; fewer were anxious. Both groups had improvement over time. By 6 months, Protocol 019 subjects had decreased Beck Depression Inventory (BDI) scores, state anxiety, stress reaction, and symptoms of depression and anxiety. Controls had decreased scores on only the BDI. Over time, the percentage meeting modified DSM III-R criteria for anxiety decreased in both groups and the proportion of Protocol 019 subjects meeting DSM III-R depression criteria decreased. After protocol modification, study subjects were less depressed and distressed than controls. Protocol 019 subjects reduced depression symptoms but controls did not. Clinical trial participation was not deleterious and may have yielded some relative psychological benefit.