Context.-Prostate cancer antigen 3 (PCA3) is a noncoding RNA that is highly overexpressed in prostate cancer (PCa) tissue and excreted in urine in patients with PCa. Objective.-To assess the clinical utility of urinary PCA3 in men at risk of PCa. Design.-We retrospectively reviewed a cohort of 271 men (median age, 63 years) with elevated prostate-specific antigen (PSA), and/or strong family history, and/or abnormal digital rectal examination findings. Diagnostic sensitivity, specificity, positive and negative predictive values (PPV, NPV), positive and negative likelihood ratios (LRþ, LR), and diagnostic odds ratio (DOR), and area under the receiver-operating characteristic curves (AUC) were evaluated. Results.-PCA3 score was a significant predictor of prostate biopsy outcome (P, .001). A PCA3 score of 30 was the optimal cutoff for our study cohort, with a diagnostic sensitivity of 72.7%, specificity of 67.5%, PPV of 47.1%, NPV of 86.2%, LRþ of 2.24, LR of 0.40, and DOR of 5.55. At this cutoff score, the PCA3 assay could avoid 57.4% of unnecessary invasive biopsies in the overall study cohort and 70.3% in the subgroup with PSA level in the ''gray zone'' (4-10 ng/mL). A logistic regression algorithm combining PCA3 with PSA increased the AUC from 0.571 for PSA-only to 0.729 (P, .001). The logistic combined marker gained the ability to discriminate low-grade from high-grade cancers. Conclusions.-Our data suggest that PCA3 improves the diagnostic sensitivity and specificity of PSA and that the combination of PCA3 with PSA gives better overall performance in identification of PCa than serum PSA alone in the high-risk population.