Refinements in prostate-specific antigen (PSA) through the use of its derivatives have augmented early detection rates of prostate cancer. However, these improvements are coupled with relatively large increases in unit cost per detected cancer. We used decision-analytic modeling to determine the most appropriate PSA derivative for population-based screening. We constructed a decision-analytic model to determine the PSA derivative with the highest cost-benefit ratio for prostate cancer screening. We defined 5 screening strategies: total PSA (tPSA) 4.0 ng/mL; free PSA/tPSA (f/tPSA) in conjunction with tPSA; and complexed PSA (cPSA) 3.8, 3.4, and 3.0 ng/mL. Prostate cancer prevalence, false-positive rates, and false-negative rates for each test strategy were calculated from a database of 2138 men. The direct costs were obtained from literature review and our department of clinical chemistry. The derivative cPSA with a positive threshold of 3.8 ng/mL was the dominant strategy. The average cost of screening was 138.93 dollars. The strategy of tPSA became dominant when the cost of cPSA was >35.00 dollars or the cost of a prostate biopsy was <67.30 dollars. To match the false-negative rate of tPSA 4.0 ng/mL, a cPSA threshold of 3.0 ng/mL is necessary (sensitivity 92.5%). At this level, the marginal cost increase over tPSA is 9.40 dollars. The dominant strategy for population-based prostate cancer screening is use of cPSA with a positive threshold of 3.8 ng/mL. The use of cPSA with a threshold of 3.0 ng/mL identifies a similar number of cancers with fewer biopsies than tPSA at 4.0 ng/mL.