Background: The decision of performing prostate biopsy in men with equivocal findings in prostate magnetic resonance imaging (MRI) is challenging as they have a low but still relevant risk of harboring significant prostate cancer (sPC). Objective: To identify clinical predictors of sPC in men with equivocal findings in prostate MRI. Secondly, we aimed to analyze the hypothetical effect of incorporating prostate-specific antigen density (PSAD) into biopsy decision. Methods: We analysed a retrospective multinational cohort from 10 academic centers comprising 1476 men who underwent combined prostate biopsy (MRI-targeted plus systematic) between 02/2012 – 04/2021 due to an equivocal lesion found in prostate MRI (Prostate Imaging Reporting and Data System 3). Primary outcome was the detection of sPC (ISUP ≥ 2) in combined biopsy. Regression analysis was performed to identify predictors for this outcome. Descriptive statistics were applied to evaluate the hypothetical effect of involving PSAD into biopsy decision. Results: 273/1476 (18.5%) men were diagnosed with sPC by combined biopsy. MRI-targeted biopsy diagnosed less sPC as compared to combined strategy: 183/1476 (12.4%) vs. 273/1476 (18.5%), p<0.01. Regression analysis confirmed age (OR 1.10 [95% CI: 1.05 – 1.15]; p < 0.001), prior negative biopsy (OR 0.46 [0.24 – 0.89]; p = 0.022) and PSAD (p<0.001) as independent predictors for sPC. Applying a PSAD cut-off of 0.15 for biopsy decision, 817/1398 (58.4%) of the biopsy procedures would have been avoided at the cost of missing sPC in 91 (6.5%) men. Limitations were the retrospective design, heterogeneity of the study cohort due to the long inclusion period and a missing central revision of MRI. Conclusions: Age, previous biopsy status and PSAD were found independent predictors of sPC in men with equivocal prostate MRI. Implementation of PSAD into biopsy decision can avoid a large proportion of unnecessary biopsies. Clinical parameters such as PSAD need validation in a prospective setting.