In preliminary trials, nefiracetam, a gamma aminobutyric compound, enhanced blood flow and improved mood following stroke. Within 3 months following stroke with major depression, 159 patients were enrolled in a double-blind trial of nefiracetam or placebo. Repeated measures analysis of covariance failed to show a significant time-by-treatment interaction. Response rates were greater than 70% and remission rates were greater than 40% for nefiracetam and placebo. The top quintile of Hamilton Depression Rating Scale scores showed significant effect after 900 mg of nefiracetam versus 600 mg or placebo. Nefiracetam was not an effective treatment for poststroke depression but produced significant improvement in the most severely depressed patients.