The need for maintenance therapy in patients with major depressive disorder (MDD) is underscored by the high likelihood of recurrence after short-term treatment. Current recommendations include treatment to remission and long-term treatment to prevent relapse and recurrence. This article will summarize the design and results of the Prevention of Recurrent Episodes of Depression with Venlafaxine for Two Years (PREVENT) study, which have been published elsewhere. PREVENT evaluated venlafaxine extended release (ER) versus placebo in two 1-year maintenance phases for prevention of recurrence in patients with MDD who responded to acute and continuation therapy. Venlafaxine ER was effective in preventing long-term recurrence when compared with placebo, with a significant reduction in likelihood of recurrence and significantly longer time to recurrence after both 1 and 2 years of maintenance therapy. Recurrence rates in the first and second maintenance periods for patients receiving placebo were similar (42 vs 45%), but recurrence rates for patients receiving venlafaxine ER decreased dramatically (23 vs 8%). The PREVENT study adds to current understanding regarding the benefits of long-term antidepressant therapy in preventing recurrence.