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Purpose: To compare various models of diffusion-weighted imaging including mono-exponential, bi-exponential, diffusion kurtosis (DK) and fractional-order calculus (FROC) models in diagnosing prostate cancer (PCa) in transition zone (TZ) and distinguish the high-grade PCa [Gleason score (GS) ≥ 7] lesions from the total of low-grade PCa (GS ≤ 6) lesions and benign prostatic hyperplasia (BPH) in TZ. Methods: 80 Patients with 103 lesions were included in this study. Nine metrics [including apparent diffusion coefficient (ADC) derived from mono-exponential model, slow diffusion coefficient (Ds), fast diffusion coefficient (Df),, and f (the fraction of fast diffusion) from bi-exponential model; mean diffusivity (MD) and mean kurtosis (MK) from DK model; diffusion coefficient (D), fractional-order derivative in space (β), and spatial metric (μ) from FROC model] were calculated. Comparisons between BPH and PCa lesions as well as between clinically significant PCa (CsPCa) (GS ≥ 7, n = 31) and clinically insignificant lesions (Cins) (GS ≤ 6 and BPH, n = 72) of these metrics were conducted. Mann–Whitney U-test and receiver operating characteristic (ROC) analysis were used for statistical evaluations. Results: The areas under the ROC curve (AUC) values of β derived from FROC model were 0.778 and 0.853 in differentiating PCa from BPH and in differentiating CS (GS ≥ 7) from Cins (GS ≤ 6 and BPH), both were the highest compared to other metrics. The AUC value of β was significantly higher than that of ADC (P = 0.009) in differentiating CS from Cins, while the differentiation between BPH and PCa did not reach the statistical significance when comparing with ADC (P = 0.089). Conclusion: Although no significant difference was found in distinguishing PCa from BPH, the metric β derived from FROC model was superior to other diffusion metrics in differentiation between CS and Cins in TZ. [ABSTRACT FROM AUTHOR]