BACKGROUND: The aim of this study was to evaluate whether MP [11C]Acetate PET-MRI enables an accurate differentiation of benign and malignant prostate tumors as well as local and distant staging. MATERIALS AND METHODS: Fifty-six consecutive patients fulfilling the following criteria were included in this IRB-approved prospective study: elevated PSA levels or suspicious findings at digital rectal examination or TRUS; and histopathological verification. All patients underwent MP [11C]Acetate PET-MRI of the prostate performed on separate scanners with PET/CT using [11C]Acetate and 3T MP MR imaging. Appropriate statistical tests were used to determine diagnostic accuracy, local and distant staging. RESULTS: MP imaging with two MRI parameters (T2w and DWI) achieved the highest sensitivity, specificity, and diagnostic accuracy of 95%, 68.8%, and 88%, with an AUC of 0.82 for primary PCa detection. Neither assessments with a single parameter (AUC, 0.54-0.79), nor different combinations with up to five parameters (AUC, 0.67-0.79) achieved equally good results. MP [11C]Acetate PET-MRI improved local staging with a sensitivity, specificity, and diagnostic accuracy of 100%, 96%, and 97% compared to MRI alone with 72.2%, 100%, and 95.5%. MP [11C]Acetate PET-MRI correctly detected osseous and liver metastases in five patients. CONCLUSIONS: MP [11C]Acetate PET-MRI merges morphologic with functional information, and allows insights into tumor biology. MP [11C]Acetate PET-MRI with two MRI-derived parameters (T2 and DWI) yields the highest diagnostic accuracy. The addition of more parameters does not improve diagnostic accuracy of primary PCa detection. MP [11C]Acetate PET-MRI facilitates improved local and distant staging, providing "one-stop" staging in patients with primary PCa, and therefore has the potential to improve therapy. PATIENT SUMMARY: In this report we investigated MP [11C]Acetate PET-MRI for detection, local and distant staging of prostate cancer. We demonstrate that MP [11C]Acetate PET-MRI with two MRI-derived parameters (T2 and DWI) achieves the best diagnostic accuracy for primary prostate cancer detection and that MP [11C]Acetate PET-MRI enables an improved local and distant staging.