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The incidence of treatment-emergent sexual dysfunction in the acute and continuation phases of the prevention of recurrent episodes of depression with venlafaxine ER for two years (PREVENT) study was assessed. Adult outpatients with recurrent major depressive disorder were randomly assigned to receive venlafaxine extended release (ER; 75–300 mg/day) or fluoxetine (20–60 mg/day). Sexual dysfunction was assessed using items from the 17-item Hamilton Rating Scale for Depression (HAM-D17) and the Inventory of Depressive Symptomatology–Self-Report (IDS-SR). The baseline rates of sexual dysfunction based on the HAM-D17 and IDS-SR items were 57.9% and 48.8%, respectively. The rates of new-onset sexual dysfunction for the venlafaxine ER–treated (44.8%, HAM-D17; 38.4%, IDS-SR) and fluoxetine-treated patients (52.9%, HAM-D17; 50.0%, IDS-SR) were similar; approximately 80% of the cases resolved during treatment. Treatment response was associated with lower rates of new-onset sexual dysfunction compared with nonresponse. The patients who remitted were the least likely to experience sexual dysfunction during antidepressant treatment.