Many studies have demonstrated that venlafaxine is an efficacious and safe treatment for major depressive disorder (MDD). This double-blind, placebo-controlled study was performed to evaluate the efficacy of venlafaxine extended-release (XR) (75-225 mg/day) in the prevention of relapse of depression. Patients with MDD who responded to an 8-week course of venlafaxine XR treatment, i.e., had a score < or = 3 on the Clinical Global Impressions scale-Severity of Illness item (CGI-S) and a 21-item Hamilton Rating Scale for Depression (HAM-D(21)) score < or = 10, were randomly assigned to receive continuation treatment (up to 6 months) with venlafaxine XR (n=161) or placebo (n=157). The main efficacy outcome measure was the number of patients who experienced a relapse of depression. Relapse was defined by either a combination of a patient meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for MDD and a CGI-S score > or = 4, two consecutive CGI-S scores > or = 4, or a final CGI-S score > or = 4 for a patient who withdrew from the study. The cumulative probability of relapse was calculated using the Kaplan-Meier method of survival analysis. During the 6-month evaluation period, significantly more patients in the placebo group had a relapse of MDD than did patients who continued treatment with venlafaxine XR. Cumulative relapse rates at 3 and 6 months were 19 and 28%, respectively, for venlafaxine XR, and 44 and 52%, respectively, for placebo. This study demonstrates that venlafaxine XR is an effective and safe continuation therapy.