BACKGROUND: This randomized, open-label, rater-blinded, multicenter study compared treatment outcomes with the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine extended release (ER) with selective serotonin reuptake inhibitors (SSRIs) in primary care patients with major depressive disorder. METHOD: Study data were collected from November 29, 2000, to March 4, 2003. Outpatients who met diagnostic criteria for major depressive disorder according to the Mental Health Screener, a computer-administered telephone interview program that screens for the most common mental disorders, and had a total score on the 17-item Hamilton Depression Rating Scale (HDRS(17)) ≥ 20 were randomly assigned to receive up to 6 months of open-label venlafaxine ER 75-225 mg/d (n = 688) or an SSRI (n = 697): fluoxetine 20-80 mg/d, paroxetine 20-50 mg/d, citalopram 20-40 mg/d, and sertraline 50-200 mg/d. The primary outcome was remission (HDRS(17) score ≤ 7) at study end point using the last-observation-carried-forward method to account for early termination. A mixed-effects model for repeated measures (MMRM) analysis evaluated secondary outcome measures. RESULTS: Fifty-one percent of patients completed the study. Month 6 remission rates did not differ significantly for venlafaxine ER and the SSRIs (35.5% vs 32.0%, respectively; P = .195). The MMRM analysis of HDRS(17) scores also did not differ significantly (P = .0538). Significant treatment effects favoring the venlafaxine ER group were observed for remission rates at days 30, 60, 90, and 135 and a survival analysis of time to remission (P = .006), as well as Clinical Global Impressions-severity of illness scale (P = .0002); Hospital Anxiety and Depression Scale-Anxiety subscale (P = .03); 6-item Hamilton Depression Rating Scale, Bech version (P = .009); and Quick Inventory of Depressive Symptomatology-Self-Report (P = .0003). CONCLUSIONS: Remission rates for patients treated with venlafaxine ER or an SSRI did not differ significantly after 6 months of treatment. Results of most secondary analyses suggested that SNRI treatment had a greater antidepressant effect versus the SSRIs studied.