Background: Psychosocial outcomes from the Prevention of Recurrent Episodes of Depression with Venlafaxine ER for Two Years (PREVENT) study were evaluated. Methods: Adult outpatients with recurrent major depressive disorder (MDD) and response or remission following 6-month continuation treatment with venlafaxine extended release (ER) were randomized to receive venlafaxine ER or placebo for 1 year. Patients without recurrence on venlafaxine ER during year 1 were randomized to venlafaxine ER or placebo for year 2. Psychosocial functioning was assessed using the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q), Life Enjoyment Scale-Short Version (LES-S), Social Adjustment Scale-Self-Report (SAS-SR) total and individual factors, Short Form Health Survey (SF-36) (vitality, social functioning, and role function-emotional items), and Longitudinal Interval Follow-up Evaluation (LIFE). Results: At year 1 end, better overall psychosocial functioning was seen among patients randomly assigned to venlafaxine ER (n = 129) vs placebo (n = 129), with significant differences at end point on SF-36 role function-emotional, Q-LES-Q, and SAS-SR total, and work, house work, social/leisure, and extended-family factor scores (p ≤ 0.05). At year 2 end, significant differences favored venlafaxine ER (n = 43) vs placebo (n = 40) on SF-36 vitality and role function-emotional, Q-LES-Q, LES-S, LIFE, and SAS-SR total, social/leisure, and extended-family factor scores (p ≤ 0.05). Limitations: Patients with chronic MDD or treatment resistance were excluded and long-term specialist care was a financial incentive for treatment compliance. Discontinuation-related adverse events may have compromised the integrity of the treatment blind. Conclusions: For patients with recurrent MDD, 2 years' maintenance therapy with venlafaxine ER may improve psychosocial functioning vs placebo. © 2010 Elsevier B.V. All rights reserved.