The purpose of this study was to summarize and compare the clinical success rates of extended-release venlafaxine, some selective serotonin reuptake inhibitors (SSRIs), and certain tricyclic antidepressants (TCAs). A meta-analytic approach was used to synthesize outcomes from published randomized controlled trials involving patients scoring > or =15 on the Hamilton Rating Scale for Depression (HAM-D) or > or =18 on the Montgomery-Asberg Depression Rating Scale (MADRS). Searches of the MEDLINE, EMBASE, and International Pharmaceutical Abstracts databases were performed, as were searches of references from retrieved articles and reviews. Drugs included in the comparison were extended-release venlafaxine (venlafaxine-XR); the SSRIs citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline; and the TCAs amitriptyline, imipramine, desipramine, and nortriptyline. Therapeutic success was defined as a 50% decrease in the HAM-D or MADRS score. Data were extracted by 2 independent evaluators, with differences resolved through consensus discussions. Weighted mean success rates were calculated for each drug class, using a random-effects model. The resulting data represent 44 trials with 63 study arms and 4033 patients with depression. Venlafaxine-XR demonstrated a 73.7% success rate, which was statistically significantly greater than that of the studied SSRIs (61.1%) and TCAs (57.9%) (P<0.001). Thus this meta-analysis of randomized controlled studies of patients with depression suggests that venlafaxine-XR is clinically superior in efficacy to SSRIs and TCAs. Venlafaxine-XR also had universally lower, though nonsignificant, dropout rates.