Background In validation studies, risk models for clinically significant prostate cancer (csPCa; Gleason score ≥3+4) combining multiparametric MRI and clinical factors have demonstrated poor calibration (over- and underprediction) and limited use in avoiding unnecessary prostate biopsies. Purpose MRI-based risk models following local recalibration were compared with a strategy that combined Prostate Imaging Data and Reporting System (PI-RADS; version 2) and prostate-specific antigen density (PSAd) to assess the potential reduction of unnecessary prostate biopsies. Materials and Methods This retrospective study included 385 patients without prostate cancer diagnosis who underwent multipara-metric MRI (PI-RADS category ≥3) and MRI-targeted biopsy between 2015 and 2019. Recalibration and selection of the best-performing MRI model (MRI-European Randomized Study of Screening for Prostate Cancer [ERSPC], van Leeuwen, Radtke, and Mehralivand models) were undertaken in cohort C1 (n = 242; 2015-2017). The impact on biopsy decisions was compared with an alternative strategy (no biopsy for PI-RADS category 3 plus PSAd < 0.1 ng/mL per milliliter) in cohort C2 (n = 143; 2018-2019). Discrimination, calibration, and clinical utility were assessed by using the area under the receiver operating characteristic curve (AUC), calibration plots, and decision curve analysis, respectively. Results The prevalence of csPCa was 38% (93 of 242 patients) and 45% (64 of 143 patients) in cohorts C1 and C2, respectively. Decision curve analysis demonstrated the highest net benefit for the van Leeuwen and Mehralivand models in C1. Used for biopsy decisions in C2, van Leeuwen (AUC, 0.84; 95% CI: 0.77, 0.9) and Mehralivand (AUC, 0.79; 95% CI: 0.72, 0.86) enabled no net benefit at a risk threshold of 10%. Up to a risk threshold of 15%, net benefit remained inferior to the PI-RADS plus PSAd strategy, which avoided biopsy in 63 per 1000 men, without missing csPCa. Without prior recalibration in C1, three of four models (MRIERSPC, Radtke, Mehralivand) were poorly calibrated and not clinically useful in C2. Conclusion The number of unnecessary prostate biopsies in men with positive MRI may be safely reduced by using a prostate-specific antigen density-based strategy. In a risk-averse scenario, this strategy enabled better biopsy decisions compared with MRI-based risk models. ©RSNA, 2021 Online supplemental material is available for this article.