Purpose: We systematically reviewed the literature on predictive factors for clinically significant prostate cancer diagnosis after prebiopsy negative magnetic resonance imaging in prostate cancer naïve patients. Materials and Methods: The MEDLINE® and Scopus® databases were searched up to March 2019. The review protocol was published in the PROSPERO database (CRD42019125549). The clinical factors and markers studied were age, prostate specific antigen, prostate specific antigen isoforms, prostate specific antigen density, PCA3, prostate volume, family history, ethnicity and risk calculators. The primary objective was to determine their predictive ability for clinically significant prostate cancer diagnosis. Secondary objectives included meta-analysis of the negative predictive value of prebiopsy negative magnetic resonance imaging when combined with these predictive factors. Results: A total of 16 studies were eligible for inclusion. Few studies reported negative predictive value of magnetic resonance imaging combined with a marker. Prostate specific antigen density was the best studied and the strongest predictor of clinically significant prostate cancer in men with prebiopsy negative magnetic resonance imaging. There were 8 studies (1,015 patients) eligible for meta-analysis of the added value of prostate specific antigen density less than 0.15 ng/ml/ml to magnetic resonance imaging in reducing the risk of missing clinically significant prostate cancer. When combined with prostate specific antigen density, overall magnetic resonance imaging negative predictive value increased from 84.4% to 90.4% in cancer naïve patients. The increase was from 82.7% to 88.7% in biopsy naïve and from 88.2% to 94.1% in previous negative biopsy subgroups. Conclusions: The use of prostate specific antigen density less than 0.15 ng/ml/ml in the presence of prebiopsy negative magnetic resonance imaging was the most useful factor to identify men without clinically significant prostate cancer who could avoid biopsy.