Purpose <p>Non-White patients are poorly represented in prostate cancer trials. MRI PI-RADS scoring was developed in primarily White populations, but prostate cancer differs in non-White men. We aimed to explore differences in PI-RADS calibration for Asian and Black men.</p> Materials and methods <p>This is a secondary analysis of PREVENT, a multi-institutional study of infection rates for transrectal vs. transperineal biopsy. We compared cancer detection for self-identifying Asian and Black men. We compared detection rates on a per-person basis, stratified by index PI-RADS lesion, to White men, using Fisher’s exact and logistic regression.</p> Results <p>Of 665/752 trial patients with PI-RADS 3-5 lesions, 88 (13%) were Black and 36 (6%) were Asian. Black men were younger at diagnosis with increased rates of overall (70% vs. 43%%, <i>P</i> = 0.004) and clinically significant prostate cancer (60% vs. 27%, <i>P</i> = 0.003) and Asian men had decreased rates of overall (0% vs. 47%, <i>P</i> = 0.004) and clinically significant prostate cancer (0% vs. 27%, <i>P</i> = 0.003) in PI-RADS 3 lesions compared to White men. On multivariable regression, Black men with PI-RADS 3/4 lesions had higher odds of overall (OR 1.17, <i>P</i> = 0.009) and clinically significant prostate cancer (OR 1.20, <i>P</i> = 0.004) and Asian men had lower odds of overall (OR 0.79, <i>P</i> = 0.01) but not clinically significant prostate cancer (OR 0.94, <i>P</i> = 0.5).</p> Conclusions <p>Black men with PI-RADS 3/4 lesions had 20% higher odds of clinically significant prostate cancer than White men while all PI-RADS 3 lesions in Asian men were negative. These findings suggest PI-RADS may require differential interpretation when assessing prostate cancer risk in non-White men.</p> Trial Registration <p>Registered at ClinicalTrials.gov (<a href="https://clinicaltrials.gov/study/NCT04843566">NCT04843566</a>, <a href="https://clinicaltrials.gov/study/NCT04843566">https://clinicaltrials.gov/study/NCT04843566</a>).</p>