Prostate Imaging-Reporting and Data System (PI-RADS) category 3 is a challenging scenario for detection of clinically significant prostate cancer (csPCa) and some tools can improve the selection of appropriate candidates for prostate biopsy.To assess the performance of the European Randomized Study of Screening for Prostate Cancer (ERSPC) magnetic resonance imaging (MRI) model, the new Proclarix test, and prostate-specific antigen density (PSAD) in selecting candidates for prostate biopsy among men in the PI-RADS 3 category.We conducted a head-to-head prospective analysis of 567 men suspected of having PCa for whom guided and systematic biopsies were scheduled between January 2018 and March 2020 in a single academic institution. A PI-RADS v.2 category 3 lesion was identified in 169 men (29.8%).csPCa, insignificant PCa (iPCa), and unnecessary biopsy rates were analysed. csPCa was defined as grade group ≥2. Receiver operating characteristic (ROC) curves, decision curve analysis curves, and clinical utility curves were plotted.PCa was detected in 53/169 men (31.4%) with a PI-RADS 3 lesion, identified as csPCa in 25 (14.8%) and iPCa in 28 (16.6%). The area under the ROC curve for csPCa detection was 0.703 (95% confidence interval [CI] 0.621-0.768) for Proclarix, 0.657 (95% CI 0.547-0.766) for the ERSPC MRI model, and 0.612 (95% CI 0.497-0.727) for PSAD (p = 0.027). The threshold with the highest sensitivity was 10% for Proclarix, 1.5% for the ERSPC MRI model, and 0.07 ng/ml/cm3 for PSAD, which yielded sensitivity of 100%, 91%, and 84%, respectively. Some 21.3%, 26.2%, and 7.1% of biopsies would be avoided with Proclarix, PSAD, and the ERSPC MRI model, respectively. Proclarix showed a net benefit over PSAD and the ERSPC MRI model. Both Proclarix and PSAD reduced iPCa overdetection from 16.6% to 11.3%, while the ERSPC MRI model reduced iPCa overdetection to 15.4%.Proclarix was more accurate in selecting appropriate candidates for prostate biopsy among men in the PI-RADS 3 category when compared to PSAD and the ERSPC MRI model. Proclarix detected 100% of csPCa cases and would reduce prostate biopsies by 21.3% and iPCa overdetection by 5.3%.We compared three methods and found that the Proclarix test can optimise the detection of clinically significant prostate cancer in men with a score of 3 on the Prostate Imaging-Reporting and Data System for magnetic resonance imaging scans.