Multiparametric magnetic resonance imaging (mpMRI) has high sensitivity but low specificity for prostate cancer (PCa) diagnosis. The aim of our systematic review was to investigate the proportion of PCa found at a repeat biopsy in patients with a negative initial prostate biopsy, despite initial positive mpMRI. Included patients had a Prostate Imaging Reporting and Data System (PI-RADS)/Likert 3–5 lesion on mpMRI prior to the initial mpMRI-targeted prostate biopsy, which was negative for PCa on histology. The main outcomes were the overall and clinically significant PCa (csPCa; International Society of Urological Pathology >1 or any provided definition) percentages at a repeat biopsy. Out of 1179 articles identified, nine studies were included (a total of 485 patients). For patients with PI-RADS 3 lesions, overall and csPCa detection percentages ranged from 0% to 80% and from 0% to 20%, respectively, while for patients with PI-RADS ≥4 lesions, the corresponding percentages were 15.4–86% and 7.7–57%. An overall cancer detection percentage of 87.5% was reported in patients with Likert 5 lesions. Limitation of our review is the small number of studies and the protocol revision that allowed studies with <50 patients. In patients with a positive MRI result and a negative initial MRI-targeted biopsy, we suggest MRI re-reading and follow-up with repeat mpMRI or the standard repeat biopsy in cases at the highest risk.