Ross EL, et al. - In this decision analytic model, adults with newly diagnosed major depressive disorder in the United States were involved in order to quantify the cost-efficiency of cognitive behavioral therapy (CBT) compared with second-generation antidepressant (SGA) for initial treatment of depression. In model projections, CBT generated higher quality-adjusted life-years (QALYs) (3 days more at 1 year and 20 days more at 5 years) along with greater costs at 1 year yet lower costs at 5 years. At 5 years, SGA had a 64% to 77% probability of having an incremental cost-efficiency ratio of $100,000 or less per QALY at 1 year whereas CBT had a 73% to 77% probability in probabilistic sensitivity analyses. Uncertainty in the relative risk for relapse of depression added the most to overall uncertainty in the optimal treatment. In conclusion, neither SGAs nor CBT gives constantly better cost-efficiency with regard to the other. Rising patient access to CBT may be assured provided many individuals' preference for psychotherapy over pharmacotherapy.