Purpose To determine the performance of a computer-aided diagnosis (CAD) system trained at characterizing cancers in the peripheral zone (PZ) with a Gleason score of at least 7 in patients referred for multiparametric magnetic resonance (MR) imaging before prostate biopsy. Materials and Methods Two institutional review board-approved prospective databases of patients who underwent multiparametric MR imaging before prostatectomy (database 1) or systematic and targeted biopsy (database 2) were retrospectively used. All patients gave informed consent for inclusion in the databases. A CAD combining the 10th percentile of the apparent diffusion coefficient and the time to peak of enhancement was trained to detect cancers in the PZ with a Gleason score of at least 7 in 106 patients from database 1. The CAD was tested in 129 different patients from database 2. All targeted lesions were prospectively scored at biopsy by using a five-level Likert score. The CAD scores were retrospectively calculated. Biopsy results were used as the reference standard. Areas under the receiver operating characteristic curves (AUCs) were computed for CAD and Likert scores by using binormal smoothing for per-lesion and per-lobe analyses, and a density function for per-patient analysis. Results The CAD outperformed the Likert score in the overall population and all subgroups, except in the transition zone. The difference was statistically significant for the overall population (AUC, 0.95 [95% confidence interval {CI}: 0.90, 0.98] vs 0.88 [95% CI: 0.68, 0.96]; P = .02) at per-patient analysis, and for less-experienced radiologists (<1 year) at per-lesion (AUC, 0.90 [95% CI: 0.81, 0.95] vs 0.83 [95% CI: 0.73, 0.90]; P = .04) and per-lobe (AUC, 0.92 [95% CI: 0.80, 0.96] vs 0.84 [95% CI: 0.72, 0.91]; P = .04) analysis. Conclusion The CAD outperformed the Likert score prospectively assigned at biopsy in characterizing cancers with a Gleason score of at least 7. © RSNA, 2018 Online supplemental material is available for this article.