OBJECTIVES: A new prostate cancer detection index was developed as a combination of serum prostate-specific antigen (PSA), free PSA, and a PSA precursor form [-2]proPSA to calculate the probability of prostate cancer and used as a diagnostic aid for men age 50 years or older with PSA 4-10 ng/mL and nonsuspicious digital rectal exam. The index has demonstrated improved specificity for detecting prostate cancer over PSA test alone in clinical trials.  The current study evaluated the cost-effectiveness of early prostate cancer detection with the index adding to PSA compared with PSA test alone from the U.S. societal perspective.   METHODS: A Markov model with probabilistic sensitivity analysis was constructed to estimate the costs and health state utilities of prostate cancer detection and consequent treatment for the annual prostate cancer screening of the male from age 50 through 75 years.  The transition probabilities, health state utilities, and prostate cancer treatment costs were derived from the published literature.  The diagnostic performance of the index was obtained from a multi-center simulation study of the index. Diagnostic related costs were obtained from the 2009 Medicare Fee Schedule.  Expected costs and effects were discounted at 3%. RESULTS: Over 25 annual screening cycles, the strategy of the index adding to PSA dominated the PSA test alone for prostate cancer detection. It was estimated to save $234, with an expected gain of 0.02 quality adjusted life years (QALYs).  The probability of the index test being cost-effective is approximately 85% at the range of $50,000/QALY to $200,000/QALY willingness to pay.  Model results are most influenced by screening starting age, discount rate, and biopsy utilization rates.  CONCLUSIONS: The index as an aid adding to PSA test may be an important strategy for prostate cancer detection as compared to using PSA alone testing.