Compared with no screening, screening primary care patients for depression one time would cost society $32,053 per QALY, screening once yearly would cost $192,444 per QALY, screening once every 3 years would cost $81,686 per QALY, and screening every 5 years would cost $50,988 per QALY. The cost-effectiveness of screening will improve if screening becomes less expensive and treatment of depression becomes more effective.