© 2015 Wiley Periodicals, Inc. Purpose To determine whether prostate-specific antigen (PSA) levels adjusted by prostate and zonal volumes estimated from magnetic resonance imaging (MRI) improve the diagnosis of prostate cancer (PCa) and differentiation between patients who harbor high-Gleason-sum PCa and those without PCa. Materials and Methods This retrospective study was Health Insurance Portability and Accountability Act (HIPAA)-compliant and approved by the Institutional Review Board of participating medical institutions. T 2 -weighted MR images were acquired for 61 PCa patients and 100 patients with elevated PSA but without PCa. Computer methods were used to segment prostate and zonal structures and to estimate the total prostate and central-gland (CG) volumes, which were then used to calculate CG volume fraction, PSA density, and PSA density adjusted by CG volume. These quantities were used to differentiate patients with and without PCa. Area under the receiver operating characteristic curve (AUC) was used as the figure of merit. Results The total prostate and CG volumes, CG volume fraction, and PSA density adjusted by the total prostate and CG volumes were statistically significantly different between patients with PCa and patients without PCa (P ≤ 0.007). AUC values for the total prostate and CG volumes, and PSA density adjusted by CG volume, were 0.68 ± 0.04, 0.68 ± 0.04, and 0.66 ± 0.04, respectively, and were significantly better than that of PSA (P < 0.02), for differentiation of PCa patients from patients without PCa. Conclusion The total prostate and CG volumes estimated from T 2 -weighted MR images and PSA density adjusted by these volumes can improve the effectiveness of PSA for the diagnosis of PCa and differentiation of high-Gleason-sum PCa patients from patients without PCa.