The potential of personalized medicine to transform the treatment of mood disorders has been widely touted in psychiatry, but has not been quantified. We estimated the costs and benefits of a putative pharmacogenetic test for antidepressant response in the treatment of major depressive disorder (MDD) from the societal perspective. Specifically, we performed cost-effectiveness analyses using state-transition probability models incorporating probabilities from the multicenter STAR*D effectiveness study of MDD. Costs and quality-adjusted life years (QALYs) were compared for sequential antidepressant trials, with or without guidance from a pharmacogenetic test for differential response to selective serotonin reuptake inhibitors (SSRIs). Likely SSRI responders received an SSRI, whereas likely nonresponders received the norepinephrine/dopamine reuptake inhibitor bupropion. For a 40-year old with MDD, applying the pharmacogenetic test and using the non-SSRI bupropion for those at higher risk for nonresponse cost $93,520 per additional QALY compared with treating all patients with an SSRI first and switching sequentially in the case of nonremission. Cost per QALY dropped below $50,000 for tests with remission rate ratios as low as 1.5, corresponding to odds ratios approximately 1.8-2.0. Tests for differential antidepressant response could thus become cost effective under certain circumstances. These circumstances, particularly availability of alternative treatment strategies and test effect sizes, can be estimated and should be considered before these tests are broadly applied in clinical settings.