Background: Epstein criteria based on sextant biopsy are assumed to be valid for 12-core biopsies. However, very scarce information is present in the current literature to support this view. Objectives: To investigate the validity of Epstein criteria for clinically insignificant prostate cancer (PCa) in a cohort of the currently utilized 12-core prostate biopsy (TRUS-Bx) scheme in patients with low-risk and intermediate-risk PCa. Method: Pathological findings were separately evaluated in the areas matching the sextant biopsy (6-core paramedian) scheme and in all 12-core schemes. Patients were divided into 2 groups according to the final pathology report of RP as true clinically significant PCa (sPCa) and insignificant PCa (insPCa) groups. Predictive factors (including Epstein criteria) and cutoff values for the presence of insPCa were separately evaluated for 6- and 12-core TRUS-Bx schemes. Then, different predictive models based on Epstein criteria with or without additional biopsy findings were created. Results: A total of 442 patients were evaluated. PSA density, biopsy GS, percentage of tumor and number of positive cores, PNI, and HG-PIN were independent predictive factors for insPCa in both TRUS-Bx schemes. For the 12-core scheme, the best cutoff values of tumor percentage and number of positive cores were found to be <= 50% (OR: 3.662) and 1.5 cores (OR: 2.194), respectively. The best predictive model was found to be that which added 3 additional factors (PNI and HG-PIN absence and number of positive cores) to Epstein criteria (OR: 6.041). Conclusions: Using a cutoff value of "1" for the number of positive biopsy cores and absence of biopsy PNI and HG-PIN findings can be more useful for improving the prediction model of the Epstein criteria in the 12-core biopsy scheme.