This study tested the effectiveness of fluoxetine as a treatment for depression in a population of methadone-maintained opioid addicts. Methadone-maintained opioid addicts (44) with depression received fluoxetine or placebo in addition to their methadone, in a double-blind randomized trial, for 12 weeks. Depressive symptoms decreased significantly overall with no significant differences between the groups treated with fluoxetine versus placebo. In addition, drug use outcomes, including cocaine and heroin self-reported use and urine toxicology were measured. There was a significant decrease in heroin use in treatment, but no medication effect. Cocaine use, was unchanged from pre-treatment to endpoint. In separately analyzing data for the subsample of subjects with the most severe depression, there was a significant decrease in depression during treatment and a significant decrease in self-reported cocaine use, but no medication effect on either depressive symptoms or on cocaine use. This study suggests that fluoxetine is not an effective agent in treating depression or cocaine use in this population.