The use of a placebo run-in phase, in which placebo responders are withdrawn from a study before random assignment to treatment condition, has been criticized as favoring the active treatment in clinical trials. We compared the effect size of randomized, placebo-controlled clinical trials (in the treatment of depression with selective serotonin reuptake inhibitors [SSRIs]) that include a placebo run-in phase with those that do not, using a meta-analytic approach. This study differed from earlier meta-analytic studies in that it considered only SSRIs and included only studies using continuous measures of depression, allowing for a more refined assessment of effect size. An extensive literature search identified 43 datasets published between 1980 and 2000 comparing placebo with SSRI and using a continuous measure of depression (usually the Hamilton Depression Rating Scale). We included only studies of at least 6 weeks' duration focusing on treatment for primary acute major depression in adults 18-65 years of age. Studies focusing on depression in specific medical illnesses were not included. Analysis of efficacy was based on 3047 subjects treated with an SSRI antidepressant and 3740 subjects treated with a placebo. There was no statistically significant difference in effect size between the clinical trials that had a placebo run-in phase followed by withdrawal of placebo responders and those trials that did not. Despite the lack of a statistically significant difference between studies of withdrawing early placebo responders and those not using this procedure, this approach is likely to continue to be used widely because it produces large absolute effect sizes. It is recommended that future studies clearly describe these procedures and report the number of subjects dropped from the study for early placebo response and other reasons.