Background: Major depressive disorder (MDD) is the most prevalent, disabling form of depression, with a high economic effect. Purpose: To assess evidence on cost-effectiveness of pharmacologic and nonpharmacologic interventions as first- and second-step treatments in patients with MDD. Data Sources: Multiple electronic databases limited to English language were searched (1 January 2015 to 29 November 2022). Study Selection: Two investigators independently screened the literature. Seven economic modeling studies fulfilled the eligibility criteria. Data Extraction: Data abstraction by a single investigator was confirmed by a second; 2 investigators independently rated risk of bias. One investigator determined certainty of evidence, and another checked for plausibility. Data Synthesis: Seven modeling studies met the eligibility criteria. In a U.S. setting over a 5-year time horizon, cognitive behavioral therapy (CBT) was cost-effective compared with second-generation antidepressants (SGAs) as a first-step treatment…