Objective: To compare the diagnostic performance between Prostate Imaging-Reporting and Data System version 2.0 (PI-RADSv2.0) and version 2.1 (PI-RADSv2.1) for clinically significant prostate cancer (csPCa) in the peripheral zone (PZ). Materials and Methods: This retrospective study included 317 patients who underwent multiparametric magnetic resonance imaging and targeted biopsy for PZ lesions. Definition of csPCa was International Society of Urologic Pathology grade ≥ 2 cancer. Area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for csPCa were analyzed by two readers. The cancer detection rate (CDR) for csPCa was investigated according to the PI-RADS categories. Results: AUC of PI-RADSv2.1 (0.856 and 0.858 for reader 1 and 2 respectively) was higher than that of PI-RADSv2.0 (0.795 and 0.747 for reader 1 and 2 respectively) (both p < 0.001). Sensitivity, specificity, PPV, NPV, and accuracy for PI-RADSv2.0 vs. PI-RADSv2.1 were 93.2% vs. 88.3% (p = 0.023), 52.8% vs. 76.6% (p < 0.001), 48.7% vs. 64.5% (p < 0.001), 94.2% vs. 93.2% (p = 0.504), and 65.9% vs. 80.4% (p < 0.001) for reader 1, and 96.1% vs. 92.2% (p = 0.046), 34.1% vs. 72.4% (p < 0.001), 41.3% vs. 61.7% (p < 0.001), 94.8% vs. 95.1% (p = 0.869), and 54.3% vs. 78.9% (p < 0.001) for reader 2, respectively. CDRs of PI-RADS categories 1-2, 3, 4, and 5 for PI-RADSv2.0 vs. PI-RADSv2.1 were 5.9% vs. 5.9%, 5.8% vs. 12.5%, 39.8% vs. 56.2%, and 88.9% vs. 88.9% for reader 1; and 4.5% vs. 4.1%, 6.1% vs. 11.1%, 32.5% vs. 53.4%, and 85.0% vs. 86.8% for reader 2, respectively. Conclusion: Our data demonstrated improved AUC, specificity, PPV, accuracy, and CDRs of category 3 or 4 of PI-RADSv2.1, but decreased sensitivity, compared with PI-RADSv2.0, for csPCa in PZ.