Background Multiparametric MRI is used for depiction of prostate cancer (PCa) but without consideration of the mechanical alteration of prostatic tissue by cancer. Purpose To investigate the diagnostic performance of stiffness and fluidity quantified with tomoelastography, a multifrequency MR elastography technique, for depiction of PCa compared with multiparametric MRI with Prostate Imaging Reporting and Data System (PI-RADS) version 2.1. Materials and Methods Prospective participants suspected to have PCa and healthy controls (HCs) underwent multiparametric MRI and tomoelastography between March 2019 and July 2020. Tomoelastography maps of shear-wave speed () and loss angle (φ) quantified stiffness and fluidity, respectively, for PCa and benign prostatic disease and for the peripheral and transition zones in HCs. Differences between entities and regions were analyzed by using analysis of variance or Kruskal-Wallis test. Diagnostic performance was assessed with area under the receiver operating characteristic curve (AUC) analysis. Results There were 73 participants with PCa (mean age, 72 years ± 7 [standard deviation]), 82 with benign prostatic disease (66 years ± 7), and 53 HCs (41 years ± 14). Mean ± standard deviation of and φ were higher in PCa (3.4 m/sec ± 0.6 and 1.3 radian ± 0.2, respectively) than in benign prostatic disease (2.6 m/sec ± 0.3 and 1.0 radian ± 0.2, respectively; < .001) and age-matched HCs (2.2 m/sec ± 0.1 and 0.8 radian ± 0.1, respectively; < .001). Incorporating and φ (AUC, 0.95; 95% CI: 0.92, 0.98) improved the diagnostic performance of PI-RADS version 2.1 (AUC, 0.85; 95% CI: 0.80, 0.91; < .001). Multiparametric MRI combined with and φ enabled detection of PCa with 95% (78 of 82 non-PCa) specificity, which was significantly higher than with use of multiparametric MRI alone (77% [63 of 82 non-PCa]; < .001). In regional analysis, combined with φ enabled differentiation of transition zone PCa from benign prostatic hyperplasia (AUC, 0.91; 95% CI: 0.83, 0.98) and peripheral zone PCa from chronic prostatitis (AUC, 0.94; 95% CI: 0.88, 1.00). Conclusion Use of tomoelastography-quantified stiffness and fluidity improved the diagnostic performance of multiparametric MRI with Prostate Imaging Reporting and Data System version 2.1 in detecting cancer in both the peripheral and transition zones. © RSNA, 2021 See also the editorial by Hectors and Lewis in this issue.