The effectiveness of selective serotonin reuptake inhibitors for depression in remitted schizophrenia has not been clearly demonstrated. A randomized, double-blind, prospective placebo-controlled study was performed of 48 subjects meeting DSM-IV criteria for both schizophrenia in remission and for a major depressive episode. Twenty-seven patients were randomized to placebo and 21 to sertraline. All subjects had a 1-week anticholinergic phase before randomization. The treatment duration was 6 weeks. Sertraline was started at 50 mg/day; this could be increased to 100 mg after 4 weeks for an inadequate response. There were no statistically significant differences in symptoms between the two groups at randomization. There were no differences in outcome between treatment groups. In both groups, between 40% and 50% of subjects showed a 50% reduction in depression score. This study does not provide support for the efficacy of sertraline in the treatment of depression in remitted schizophrenia. The small sample size limits the strength of the conclusions that can be drawn from this study. The study design called for a sample size of 96 on the basis of an expected placebo response rate of 30%. Recruitment for the study was difficult because of the placebo design. The placebo response was 50%. Clinicians and patients underestimate the strength of the placebo response and may overestimate the risk of participating in such a study. Testing the efficacy of widely accepted but poorly evaluated treatments should be a research priority. Future studies require a larger sample size and longer duration of treatment.