OBJECTIVE: The authors’ goal was to determine if prescription of antidepressant medication plus olanzapine initiates a more rapid response than prescription of antidepressant alone. METHOD: Twenty patients with major depression were studied. For 2 weeks the patients were blindly assigned to receive antidepressant plus olanzapine or antidepressant plus placebo. After 2 weeks, olanzapine augmentation was initiated for patients who did not improve with placebo augmentation. Response to medication was measured primarily by Hamilton Depression Rating Scale score. Other measures were the CORE, Clinical Global Impression, Beck Depression Inventory, and Daily Rating Schedule. RESULTS: Hamilton depression scores improved nonsignificantly in response to olanzapine combination therapy, but that trend was not evident on any secondary measure. Four patients who did not improve while receiving antidepressant and placebo showed rapid remission following late olanzapine augmentation. CONCLUSIONS: Failure to demonstrate any benefit from initial combination therapy may reflect an underpowered rather than a negative study. The distinct impact of late olanzapine augmentation suggests that pretreatment with an antidepressant may be required to facilitate a rapid antidepressant response to combined treatment.