To evaluate the usefulness of histogram analysis of stretched exponential model (SEM) on diffusion-weighted imaging (DWI) in evaluating clinically significant prostate cancer (CSC).A total of 85 patients with prostate cancer underwent 3 T multiparametric MRI, followed by radical prostatectomy. Histogram parameters of the tumor from the SEM (distributed diffusion coefficient [DDC] and α) and the monoexponential model (MEM; apparent diffusion coefficient [ADC]) were evaluated. The associations between parameters and Gleason score (GS) or Prostate Imaging Reporting and Data System (PI-RADS) v2 were evaluated. The area under the receiver operating characteristics curve (AUC) was calculated to evaluate diagnostic performance of parameters in predicting CSC.The values of histogram parameters of DDC and ADC were significantly lower in patients with CSC than in patients without CSC ( < 0.05), except for skewness and kurtosis. The value of the 25 percentile of α was significantly lower in patients with CSC than in patients without CSC ( = 0.014). Histogram parameters of ADC and DDC had significant weak to moderate negative associations with Gleason score (GS) or PI-RADS v2 ( < 0.001), except for skewness and kurtosis. For predicting CSC, the AUCs of mean ADC (0.856), 50 percentile DDC (0.852), and 25 percentile α (0.707) yielded the highest values compared to other histogram parameters from each group.Histogram analysis of the SEM on DWI may be a useful quantitative tool for evaluating CSC. However, the SEM did not outperform the MEM.Histogram parameters of SEM may be useful for evaluating CSC.