To investigate the detection and predictors of prostate cancer (PCA) and clinically significant prostate cancer (csPCA) in patients with positive multiparametric MRI (mpMRI) followed by a negative MRI - guided target biopsy (TB) and systematic biopsy (SB). This retrospective multicenter study included 694 patients from 10 tertiary referral centers with an initial positive mpMRI (PI-RADS ≥ 3) and negative results on both MRI-TB and SB. Patients were classified into three groups based on follow-up: Group 1 (prostate re-biopsy without new mpMRI), Group 2 (standardized second prostate mpMRI and subsequent re-biopsy), and Group 3 (follow-up with mpMRIs and biopsy based on clinical and radiological triggers). The primary outcomes were the detection of any PCA and csPCA during follow up. Study groups were compared according to their probability of PCA and csPCA assessed with the ERSPC-MRI risk calculator. Statistical analysis included Kaplan - Meier analysis, Cox regression, and multivariable analysis for the detection of (cs)PCa. The overall detection of PCA and csPCA was 26.8% and 19.3%, respectively, with varying rates in different PI-RADS groups. Group 3 had the highest 2-year and 5-year PCA-free survival (94 and 84%) and csPCA - free survival (96 and 86%). Multivariable analysis revealed a significantly higher risk of PCA and csPCA in Group 1 and 2 compared to Group 3 (p < 0.01). Clinical and radiological predictors for PCA and csPCA included higher age, prostate volume, PI-RADS score, the presence of atypical small acinar proliferation (ASAP), and a smaller number of TB and SB performed during the initial biopsy. Study limitations, include the retrospective design and reliance on clinical and radiological triggers for follow-up decisions. Patients with positive mpMRI but negative TB and SB results exhibit varying rates of PCA and csPCA depending on the follow up scheme. Tailored follow-up strategies are essential for optimal management in this clinical scenario.