OBJECTIVES: Recent approval by the US Food and Drug Administration of three atypical antipsychotics--aripiprazole, quetiapine, and olanzapine‑‑as adjunctive therapy in adult patients with MDD makes examination of their cost-effectiveness important from a payer perspective. METHODS: We developed a decision-analytic model to estimate expected outcomes and economic costs in adults with MDD receiving aripiprazole (2-20 mg/day), quetiapine (150 mg/day or 300 mg/day), or olanzapine (6-18 mg/day as a fixed-dose combination with fluoxetine [50 mg]) as adjunctive therapy to ADT.  Cost-effectiveness was assessed in terms of the ratio of the expected difference in costs of MDD-related care to the expected difference in clinical response (≥50% reduction from baseline in Montgomery-Asberg Depression Rating Scale) at 6 weeks (i.e., cost per additional responder).  Expected costs of MDD-related care included study medication, and monitoring and treatment of adverse events.  Model parameters were estimated using data from Phase III trials and published literature. RESULTS: With ADT alone, the expected rate of clinical response at 6 weeks was estimated to be 30%.  Adjunctive therapy with aripiprazole, quetiapine 150 mg/day, quetiapine 300 mg/day, and olanzapine was estimated to increase clinical response at 6 weeks to 49%, 34%, 38%, and 45%, respectively.  Costs of MDD-related care over 6 weeks were estimated to be $164 for ADT alone, $714 for aripiprazole, $498 for quetiapine 150 mg/day, $606 for quetiapine 300 mg/day, and $669 for olanzapine.  Cost per additional responder (vs ADT) was estimated to be $2798 for aripiprazole, $7996 for quetiapine 150 mg/day, $5706 for quetiapine 300 mg/day, and $3324 for olanzapine.  The cost-effectiveness of adjunctive therapy was most sensitive to the estimated rate of clinical response at 6 weeks and the cost of adjunctive therapy. CONCLUSIONS: Adjunctive therapy with atypical antipsychotics substantially increases clinical response at 6 weeks.  Cost per additional responder is lower for aripiprazole than quetiapine or olanzapine.