Objective: To assess the value of best clinical judgment (BCJ) and the prostate cancer gene 3 (PCA3) assay in guiding the decision to perform a repeat prostate biopsy (PBx) after a previous negative PBx. Materials and Methods: Using the RAND/UCLA Appropriateness Method, 12 European urologists established recommendations (BCJ) for the appropriateness of PBx according to the prostate-specific antigen level, digital rectal examination findings, number of previous negative PBxs, prostate volume, and life expectancy, with and without consideration of the PCA3 scores. These recommendations were applied to 1024 subjects receiving placebo in the Reduction by Dutasteride of Prostate Cancer Events trial, including men with a previous negative PBx, a baseline prostate-specific antigen level of 2.5-10 ng/mL, and a PCA3 test performed before the protocol-mandated 2- and 4-year repeat PBxs. Three scenarios (ie, BCJ alone, BCJ with PCA3, and the PCA3 score alone) were tested for their ability to reduce the repeat PBx rate versus missing Gleason sum ≥7 prostate cancer (PCa). Results: BCJ with PCA3 would have avoided 64% of repeat PBxs compared with 26% for BCJ alone and 55% for PCA3 alone (cutoff score 20). Of 55 PCa cases (Gleason sum ≥7), 13 would have been missed using BCJ alone compared with 7 using PCA3 (cutoff score 20) alone and 8 using BCJ plus PCA3. The diagnostic accuracy for Gleason sum ≥7 PCa of the BCJ with PCA3 scenario was superior to that of the other scenarios, with a negative predictive value of 99%. Conclusion: Application of the BCJ together with PCA3 testing can reduce the number of repeat PBxs while maintaining the sensitivity to detect Gleason sum ≥7 PCa.