In this study we tested whether initial clinical change (ICC) and initial subjective response (ISR) predict the outcome of antidepressant pharmacotherapy and whether ICC and ISR as predictors reflect specific pharmacological actions or a placebo effect. Forty patients with major depression were treated with three different antidepressants for 4 weeks. Overall clinical change and final subjective response were taken as outcome criteria. The patients were randomly assigned to two subgroups in a double-blind design. Initially, one group received the active drug and the other placebo. Afterwards, all patients were given the active drug. Significant correlations were found between ICC and ISR and at least one of the outcome criteria in the total sample and in each subgroup. The findings show that ICC and ISR may be significant predictors of outcome. The predictive value of ICC and ISR is not due to initial pharmacological effects, but to non-specific treatment factors.