Sexual dysfunction has been reported as an unwanted effect associated with selective serotonin reuptake inhibitors therapy, but the nature and frequency of such effects have not been characterized systematically. Sexual function was assessed in depressed patients participating in a multicenter trial of acute and continuation fluoxetine therapy using a 4-item self-rated scale. Patients were evaluated at study entry, after 13 weeks of fluoxetine 20 mg daily, and during 25 weeks of continuation therapy with fluoxetine 20 mg daily, fluoxetine 90 mg weekly, or placebo. In a 13-week open-label trial, among 501 patients who met Diagnostic and Statistical Manual of Mental Disorders criteria for depression, 51.6% of women and 40.6% of men reported improvement, 35.0% of women and 41.9% of men reported no change, and 13.4% of women and 17.4% of men reported worsening in overall sexual function. During double-blind continuation therapy, there were no statistically significant differences in change in sexual function between treatments. Worsened sexual function that occurred during continuation treatment was strongly associated with worsened depressive symptoms. Depression is associated with sexual dysfunction, and improvement in sexual functioning related to the antidepressant effects of fluoxetine may be more common than drug-associated deterioration in sexual function. Among patients who report worsening, effects may be most pronounced on orgasm. Deterioration in sexual function does not appear to be a late-onset drug-specific event, but is strongly related to worsening depressive symptoms.