OBJECTIVES: Major depressive disorder (MDD) is frequently debilitating. The American Psychiatric Association recommends adjunctive atypical antipsychotics (AA) as a treatment option when response to antidepressants is inadequate. This study compared medical costs and hospitalizations among MDD patients treated with FDA-approved adjunctive AA.  METHODS: This retrospective analysis used medical and pharmacy claims data and enrollment information from a large US health plan. Subjects were adult commercial enrollees with depression (ICD-9-CM 296.2x, 296.3x, 296.82, 300.4, 311) augmenting antidepressant therapy with an AA (aripiprazole, olanzapine, or quetiapine) from 1/1/2004-1/31/2010. Subjects were continuously enrolled for 6-month pre- and 12-month post-augmentation periods. Those with schizophrenia or bipolar disorder were excluded.   Post-augmentation outcomes were all-cause and mental health (MH-) related medical costs and hospitalizations.  Costs and hospitalizations were modeled with generalized linear models (gamma distribution, log link) and logistic regression, respectively. Regressions controlled for dose, demographics, and general and MH-related health status. Outpatient pharmacy costs were not assessed. RESULTS: 10,292 subjects were identified across AA cohorts: aripiprazole, n=3,849; olanzapine, n=1,033; and quetiapine, n=5,410. Mean age was 44.1±11.6 years and 70.3% were female. Compared with the aripiprazole cohort, regression results showed that the olanzapine cohort had higher predicted all-cause (1.22, p=0.004) and MH-related (1.33, p=0.002) medical cost ratios and higher odds of all-cause (1.58, p<0.001) and MH-related (1.81, p<0.001) hospitalizations. The quetiapine cohort also had higher predicted all-cause (1.27, p<0.001) and MH-related (1.23, p=0.001) medical cost ratios and higher odds of all-cause (1.65, p<0.001) and MH-related (1.78, p<0.001) hospitalizations. Mean predicted all-cause and MH-related medical costs, respectively, were $11,401 and $2,495 for aripiprazole, $13,905 and $3,316 for olanzapine, and $14,513 and $3,072 for quetiapine. CONCLUSIONS: Compared with adjunctive olanzapine or quetiapine, adjunctive aripiprazole was associated with lower mean all-cause and MH-related medical costs and with lower odds of all-cause and MH-related hospitalizations in patients with depression.