PURPOSE:We performed a cost-effectiveness analysis using the PHI (Prostate Health Index), 4Kscore®, SelectMDx™ and the EPI (ExoDx™ Prostate [IntelliScore]) in men with elevated prostate specific antigen to determine the need for biopsy. MATERIALS AND METHODS:We developed a decision analytical model in men with elevated prostate specific antigen (3 ng/ml or greater) in which 1 biomarker test was used to determine which hypothetical individuals required biopsy. In the current standard of care strategy all individuals underwent biopsy. Model parameters were derived from a comprehensive review of the literature. Costs were calculated from a health sector perspective and converted into 2017 United States dollars. RESULTS:The cost and QALYs (quality adjusted life-years) of the current standard of care, which was transrectal ultrasound guided biopsy, was $3,863 and 18.085, respectively. Applying any of the 3 biomarkers improved quality adjusted survival compared to the current standard of care. The cost of SelectMDx, the PHI and the EPI was lower than performing prostate biopsy in all patients. However, the PHI was more costly and less effective than the SelectMDx strategy. The EPI provided the highest QALY with an incremental cost-effectiveness ratio of $58,404 per QALY. The use of biomarkers could reduce the number of unnecessary biopsies by 24% to 34% compared to the current standard of care. CONCLUSIONS:Applying biomarkers in men with elevated prostate specific antigen to determine the need for biopsy improved quality adjusted survival by decreasing the number of biopsies performed and the treatment of indolent disease. Using SelectMDx or the EPI following elevated prostate specific antigen but before proceeding to biopsy is a cost-effective strategy in this setting.