Most guidelines for major depressive disorder recommend initial treatment with either a second-generation antidepressant (SGA) or cognitive behavioral therapy (CBT). Although most trials suggest that these treatments have similar efficacy, their health economic implications are uncertain.To quantify the cost-effectiveness of CBT versus SGA for initial treatment of depression.Decision analytic model.Relative effectiveness data from a meta-analysis of randomized controlled trials; additional clinical and economic data from other publications.Adults with newly diagnosed major depressive disorder in the United States.1 to 5 years.Health care sector and societal.Initial treatment with either an SGA or group and individual CBT.Costs in 2014 U.S. dollars, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios.In model projections, CBT produced higher QALYs (3 days more at 1 year and 20 days more at 5 years) with higher costs at 1 year (health care sector, $900; societal, $1500) but lower costs at 5 years (health care sector, -$1800; societal, -$2500).In probabilistic sensitivity analyses, SGA had a 64% to 77% likelihood of having an incremental cost-effectiveness ratio of $100 000 or less per QALY at 1 year; CBT had a 73% to 77% likelihood at 5 years. Uncertainty in the relative risk for relapse of depression contributed the most to overall uncertainty in the optimal treatment.Long-term trials comparing CBT and SGA are lacking.Neither SGAs nor CBT provides consistently superior cost-effectiveness relative to the other. Given many patients' preference for psychotherapy over pharmacotherapy, increasing patient access to CBT may be warranted.Department of Veterans Affairs, National Institute of Mental Health.