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PI-RADS™, version 2 stipulates that dynamic contrast enhanced imaging should be used to classify diffusion-weighted imaging score 3 peripheral zone lesions as PI-RADS score 3 (dynamic contrast enhanced imaging negative or nonenhancing) or 4 (dynamic contrast enhanced imaging positive or enhancing). However, to our knowledge it is unknown whether dynamic contrast enhanced imaging separates lesions into clinically meaningful pathological groups. We examined whether dynamic contrast enhanced imaging would improve the detection of clinically significant cancer.We identified patients without a prior diagnosis of prostate cancer who underwent multiparametric magnetic resonance imaging-transrectal ultrasound fusion targeted biopsy of peripheral zone lesions with a diffusion-weighted imaging score of 3 or 4. Each lesion was grouped into 1 of 3 classifications, including group 1—diffusion-weighted imaging score 3/nonenhancing/PI-RADS score 3, group 2—diffusion-weighted imaging score 3/enhancing/PI-RADS score 4 or group 3—diffusion-weighted imaging score 4/PI-RADS score 4. We measured the rate of grade group 2 or greater pathology detected for each lesion group with subgroup analyses in patients with vs without prior negative systematic biopsy.We identified a total of 389 peripheral zone diffusion-weighted imaging score 3 or 4 lesions in 290 patients. The rate of grade group 2 or greater cancer on biopsy for group 1, 2 and 3 lesions was 8.9%, 21% and 36.5%, respectively (p <0.03). The rate of grade group 2 or greater pathology was higher in group 2 than group 1 lesions in patients with prior negative systematic prostate biopsy (28% vs 5.0%, p <0.001) but not in those without such a biopsy (16% vs 12%, p = 0.5). Group 3 lesions had a higher rate of grade group 2 or greater cancer than group 2 lesions in the biopsy naïve subgroup (46% vs 16%, p = 0.001). However, the rates were similar in patients with prior negative systematic prostate biopsy (27% vs 28%, p = 0.9).Diffusion-weighted imaging score 3 peripheral zone lesions were more likely to be clinically significant cancer (grade group 2 or greater) if they were dynamic contrast enhanced T1-weighted imaging positive. That was most apparent in patients with a prior negative systematic prostate biopsy. In such patients including a dynamic contrast enhanced sequence in multiparametric magnetic resonance imaging allowed for optimal lesion risk stratification.