OBJECTIVE: To compare the cost-effectiveness of PSA screening for the detection of prostate cancer in the United States versus no screening. Incremental Cost per Quality-Adjusted Life Year (QALY) using a lifetime decision model was used. METHODS: Estimates of cost, utility and probabilities were taken from literature, clinical experts and the Bureau of Labor Statistics. Cancer specific mortality rates were determined by the grade of the disease. The DEALE method was used to calculate average life expectancy of men in the general population, using the life tables from the CDC. A cohort of men stratified into six age groups: 45-59, 50-54, 55-59, 60-64, 65-69, and 70-74. The time horizon was a lifetime; future values discounted at 3% and the perspective was societal. RESULTS: In 2002 USD, a one time screening of each age group was found to be cost-effective. The incremental cost-effectiveness ratio (ICER) ranged from $5,291 per life year saved for men aged 45-49 to $12,219 per life year saved for men aged 70-74. After adjusting for quality of life, we found that the ICER ranged from $6,452/QALY to $14,902/QALY for men aged 70-74. Results of sensitivity analysis show lowering the positive predicted value of the PSA test by approximately 30% increased cost/QALY from 8-12%, increasing it by about 20% decreases the ratio about 3-5%. The model remained cost-effective after varying the cost of Radical Prostatectomy, the mortality from surgery and the percentage of local prostate cancers found by screening. CONCLUSION: This model found a one time PSA screening for prostate cancer in each age group to be cost-effective relative to no screening.