Objectives <p>To assess whether the peripheral-zone T2-weighted signal-intensity index (PZ_SI2) detects prostate cancer (PCa) and clinically significant prostate cancer (CsPCa) in PI-RADS v2.1 ≥ 3 peripheral-zone lesions, and whether reduce unnecessary biopsies.</p> Methods <p>A single-center retrospective analysis was performed on 83 patients (with a total of 83 lesions) who underwent preoperative prostate magnetic resonance imaging (MRI) and were confirmed by both systematic and targeted biopsies. PZ_SI2 was calculated as the ratio of T2WI signal intensity in the peripheral zone lesion to that of the obturator internal muscle. Diagnostic performance was assessed using ROC analysis, the area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV), false-positive rate (FPR), and false-negative rate (FNR) were calculated.</p> Results <p>In lesion-based analysis, the detection rates of PCa and CsPCa for peripheral zone lesions PI-RADS v2.1 ≥ 3 were 54%, 51%, respectively. PZ_SI2 demonstrated high diagnostic performance for detecting PCa and CsPCa in PI-RADS ≥ 3 peripheral-zone lesions, with AUCs of 0.89 (95% CI: 0.80–0.95) for PCa and 0.86 (95% CI: 0.76–0.92) for CsPCa. The optimal thresholds of PZ_SI2 for detecting PCa and CsPCa using Youden’s index were ≤ 5.25. For detecting PCa, the sensitivity was 0.93 (95% CI: 0.82–0.99), specificity was 0.84 (95% CI: 0.69–0.94), and for detecting CsPCa, the sensitivity was 0.93 (95% CI: 0.81–0.99), specificity was 0.78 (95% CI: 0.62–0.89). Using PZ_SI2 ≤5.25 as the biopsy threshold of peripheral-zone PI-RADS ≥ 3 lesions could reduce 42% (35/83) of biopsies, while maintaining an 81% PPV for CsPCa, the FPR was 22%, and the FNR was 7%.</p> Conclusion <p>PZ_SI2 may serve as a useful feature for discriminating prostate cancer from benign lesions among peripheral zone PI-RADS ≥ 3, and may contribute to reducing unnecessary biopsies.</p>