© 2018 Elsevier Inc. Magnetic resonance imaging (MRI)/ultrasound fusion–targeted biopsy (TB) has been shown to more accurately identify higher-grade prostate cancers compared with standard-of-care systematic sextant prostate biopsy (SB). However, occasional false-positive imaging findings occur. We investigated the histologic findings associated with false-positive prostate MRI findings. A retrospective review was performed on our surgical pathology database from 2014 to 2017 selecting patients with no cancer detected on TB with concurrent SB after at least 1 prior benign SB session. Histologic features evaluated included percentage of core involvement by chronic inflammation, percentage of core composed of stroma, percentage of glands involved by atrophy, and presence of the following features: acute or granulomatous inflammation, stromal nodular hyperplasia, adenosis, squamous metaplasia, basal cell hyperplasia, and presence of skeletal muscle. Histologic findings were compared between TB and concurrent SB. We identified 544 patients who underwent TB. Of these, 41 patients, including 62 targeted lesions, met criteria. Compared with SB tissue, the mean percentage of stroma was increased in TB (P =.02). Basal cell hyperplasia was also found to be more common on TB (P =.02). Both high percentage of stroma (P =.046) and presence of basal cell hyperplasia (P =.038) were independent predictors on multivariate analysis. The combination of high chronic inflammation, high stroma, acute inflammation, and basal cell hyperplasia was associated with TB (P =.001). Atrophic glands and chronic inflammation showed a positive correlation (r = 0.67, P =.003), which was especially seen in high prostate imaging reporting and data system lesions. Specific benign histologic entities are associated with false-positive findings on prostate MRI.