Prostate-specific antigen (PSA) screening for prostate cancer is controversial. Experts have suggested more personalized or more conservative strategies to improve benefit-risk tradeoffs, but the value of these strategies-particularly when combined with increased conservative management for low-risk cases-is uncertain.To evaluate the potential cost-effectiveness of plausible PSA screening strategies and to assess the value added by increased use of conservative management among low-risk, screen-detected cases.A microsimulation model of prostate cancer incidence and mortality was created. A simulated contemporary cohort of US men beginning at 40 years of age underwent 18 strategies for PSA screening. Treatment strategies included (1) contemporary treatment practices based on age and cancer stage and grade observed in the Surveillance, Epidemiology, and End Results program in 2010 or (2) selective treatment practices whereby cases with a Gleason score lower than 7 and clinical T2a stage cancer or lower are treated only after clinical progression, and all other cases undergo contemporary treatment practices. National and trial data on PSA growth, screening and biopsy patterns, incidence of prostate cancer, treatment distributions, treatment efficacy, mortality, health-related quality of life, and direct medical expenditure were analyzed. Data were collected from March 18, 2009, to August 15, 2014, and analyzed from November 20, 2012, to December 11, 2015.Eighteen screening strategies that vary by start and stop age, screening interval, and criteria for biopsy referral and contemporary or selective treatment practices.Life-years (LYs), quality-adjusted life-years (QALYs), direct medical expenditure, and cost per LY and QALY gained.All 18 screening strategies were associated with increased LYs (range, 0.03-0.06) and costs ($263-$1371) compared with no screening, with the cost ranging from $7335 to $21 649 per LY. With contemporary treatment, only strategies with biopsy referral for PSA levels higher than 10.0 ng/mL or age-dependent thresholds were associated with increased QALYs (0.002-0.004), and only quadrennial screening of patients aged 55 to 69 years was potentially cost-effective in terms of cost per QALY (incremental cost-effectiveness ratio, $92 446). With selective treatment, all strategies were associated with increased QALYs (0.002-0.004), and several strategies were potentially cost-effective in terms of cost per QALY (incremental cost-effectiveness ratio, $70 831-$136 332).For PSA screening to be cost-effective, it needs to be used conservatively and ideally in combination with a conservative management approach for low-risk disease.