© 2017, Springer Science+Business Media New York (outside the USA). Purpose: The purpose of the study is to differentiate granulomatous prostatitis (GP) from high-grade prostate cancer (PCa) based on clinical findings and imaging characteristics on multiparametric MRI (MP-MRI). Methods: Pathology from patients undergoing MRI/US fusion-guided prostate biopsies between 2014 and 2015 was reviewed. Five patients with biopsy proven GP were identified as well as 15 patients with biopsy-proven Gleason score ≥4 + 3 = 7 PCa. Patients were matched for age, serum PSA level, and prebiopsy-assigned MP-MRI cancer suspicion scores. MP-MRI studies were reviewed to identify findings that would differentiate GP from PCa in patients who had equally high suspicion scores based upon imaging characteristics. Results: All five patients with GP on MR/US fusion-targeted biopsies were assigned a PIRADS 4 or 5 suspicion score. There were equally high suspicion scores on MP-MRI for both groups (p = 0.57). Re-evaluation of the MRI characteristics of the 5 GP patients and 15 matched controls who had pathologically proven Gleason score ≥4 + 3 = 7 PCa on targeted biopsy demonstrated statistically lower mean ADC values within the index targeted lesion for PCa vs. GP (p = 0.002) Qualitatively, no patients with GP on biopsy had imaging evidence of higher-staged disease, while 33% of patients in the high-risk PCa cohort demonstrated at least one high-stage feature (p = 0.003). Conclusion: Patients with GP routinely have MRIs with moderate to high levels of suspicion for harboring PCa. Re-evaluation of these patients’ imaging demonstrated characteristics including significantly higher ADC values and absence of high-stage features, which may help differentiate areas of GP from PCa in the future.