OBJECTIVE: This analysis was designed to compare improvements in health-related quality of life (HRQoL) measured by the General Life Functioning scale (GLF) in patients with major depressive disorder (MDD) treated with venlafaxine extended release (XR), sertraline, or placebo. METHODS: Data were pooled from two identical multicenter, randomized, double-blind, placebo-controlled studies of flexible-dose venlafaxine XR (37.5-300mg/day) and sertraline (50-200mg/day) in 10-week treatment of DSM-IV MDD (N=1352). Average per-item score (ranging from one being ‘best' and six being ‘worst') of overall GLF and its three subscales (well-being, coping, and closeness) were used to assess functioning. Improvement was measured by reduction from baseline score at the end of the study, and was analyzed using ANCOVA controlling for study center and baseline values. In addition, the overall trend of weekly scores during treatment was evaluated using repeated measures mixed model. RESULTS: At baseline, GLF per-item score had a median of four. At the end of study, venlafaxine XR was associated with significant (P<0.0001) improvement (as measured by per-item score reduction from baseline) compared with placebo on GLF total score (1.0 vs. 0.6) and all three subscales: well-being (1.2 vs. 0.7), coping (1.0 vs. 0.6), and closeness (0.8 vs. 0.4). The weekly trends of total and subscale scores were also significantly better for venlafaxine XR compared with placebo (all P<0.0025). Sertraline/placebo differences on all measures were also statistically significant but numerically smaller. CONCLUSION: Venlafaxine XR and sertraline treatment were associated with significant improvement on HRQoL measured by GLF in depressed patients.