Objective:To explore independent risk factors and risk stratification for diagnosis of clinically significant prostate cancer (CsPCa) in biopsy-naive patients with nonsuspicious multiparametric magnetic resonance imaging (mpMRI).Methods:The data of 549 patients who underwent initial systematic biopsy (SB) in the First Affiliated Hospital of Soochow University, the Second Affiliated Hospital of Soochow University and Traditional Chinese Medicine Hospital of Kunshan between October 2015 and January 2021 were retrospectively reviewed. Nonsuspicious mpMRI was defined as Prostate Imaging-Reporting and Data System (PI-RADS)≤2. All patients received systematic 12 core prostate biopsy, 278 of them by transperineal and 271 by transrectal biopsies. The median age of the patients was 67 (62, 73) years, the median prostate specific antigen (PSA) was 9.01 (6.15, 13.64) ng/ml, the median prostate volume was 48.41 (35.85, 64.28) ml, and 54 patients were positive in digital rectal examination (DRE). Taking CsPCa as the outcome index, receiver operating characteristic (ROC) analysis was performed on age, tPSA, f/tPSA and PSA density (PSAD) to obtain the optimal cut-off value, and logistics regression was used to explore the independent risk factor of CsPCa in mpMRI negative patients. The optimal cut-off value when the negative predictive value (NPV) of mpMRI diagnosis of CsPCa was 100%, was taken as the protective factor, and the risk stratification model was finally proposed.Results:Of all 549 cases, 44 were CsPCa, 35 were clinically insignificant prostate cancer and 470 were non-prostate cancer. There were significant differences in age (71 vs. 67 years old), tPSA (11.95 vs. 8.75 ng/ml), PSAD [0.31 vs. 0.18 ng/(ml·cm 3)], f/tPSA (0.12 vs. 0.16) and DRE positive rate (38.6% vs. 7.3%) between CsPCa group and non-CsPCa group ( P<0.01). Cut-off values were taken in ROC analysis when the Youden index was at its maximum. The optimal cut-off values of each continuous variable were: age=65 years, tPSA=10ng/ml, f/tPSA=0.2 and PSAD=0.15 ng/(ml·cm 3). Multivariate analysis showed that ages over 65 years ( OR=3.43, 95% CI 1.55-7.58, P=0.002), f/t PSA ratio<0.2 ( OR=3.84, 95% CI 1.28-11.56, P=0.016), PSAD>0.15 ng/(ml·cm 3) ( OR=3.60, 95% CI 1.13-11.51, P=0.03) and positive DRE ( OR=5.20, 95% CI 2.39-11.32, P<0.001) were independent risk factors of CsPCa. When NPV was 100%, the cut-off values were taken as the protective factors: age≤55 years, f/tPSA≥0.3, PSAD≤0.1 ng/(ml·cm 3). Combined with independent risk factors, preliminary risk stratification was conducted: those with ≥2 high risk factors were considered as high risk group, those with ≥2 protective factors were considered as low risk group, and the middle region was considered as medium risk group. Conclusions:Patients with age>65 years, f/tPSA<0.2, PSAD > 0.15 ng/(ml·cm 3) and DRE positive are independent risk factors of CsPCa in mpMRI negative patients. Patients in the high-risk group were recommended to undergo prostate biopsy, while patients in the low-risk group could be considered to avoid biopsy.