OBJECTIVE: To evaluate the cost-effectiveness of screening for depression in patients with acute coronary syndrome (ACS) and no history of depression. METHODS: Cost-effectiveness analysis of a randomized trial enrolling 1500 patients with ACS between 2013 and 2017. Patients were randomized to no screening, screening and notifying the primary care provider (PCP), and screening, notifying the PCP, and providing enhanced depression treatment. Outcomes measured were Healthcare utilization, costs, and incremental cost-effectiveness ratios. RESULTS: 7.1% of patients screened positive for depressive symptoms. There was no significant difference in usage of mental health services, cardiovascular tests and procedures, and medications. Mean total costs in No Screen group ($7440), in Screen, Notify, and Treat group ($6745), and in Screen and Notify group ($6204). The difference was only significant in the Screen and Notify group versus the No Screen group (-$1236, 95% confidence interval -$2388 to -$96). Because mean QALYs were higher (+0.003 QALY in Screen and Notify; +0.004 QALYs in Screen, Notify, and Treat) and mean total costs were lower in both intervention groups, these interventions were cost-effective. There was substantial uncertainty because confidence intervals around cost differences were wide and QALY effects were small. CONCLUSION: Depression screening strategies for patients with ACS may be modestly cost-effective.