Background Prostatic ductal adenocarcinoma (DAC) is an aggressive histologic variant of prostate cancer that often warrants multimodal therapy and poses a significant diagnostic challenge clinically and at imaging. Purpose To develop multiparametric MRI criteria to define DAC and to assess their diagnostic performance in differentiating DAC from prostatic acinar adenocarcinoma (PAC). Materials and Methods Men with histologically proven DAC who had multiparametric MRI before radical prostatectomy were retrospectively identified from January 2011 through November 2018. MRI features were predefined using a subset of nine DACs and then compared for men with peripheral-zone DACs 1 cm or greater in size and men with matched biopsy-confirmed International Society of Urological Pathology grade group 4-5 PAC, by four independent radiologists blinded to the pathologic diagnosis. Diagnostic performance was determined by consensus read. Patient and tumor characteristics were compared by using the Fisher test, t-tests, and Mann-Whitney U test. Agreement (Cohen κ) and sensitivity analyses were also performed. Results There were 59 men with DAC (median age, 63 years [interquartile range, 56, 67 years]) and 59 men with PAC (median age, 64 years [interquartile range, 59, 69 years]). Predefined MRI features, including intermediate T2 signal, well-defined margin, lobulation, and hypointense rim, were detected in a higher proportion of DACs than PACs (76% [45 of 59] vs 5% [three of 59]; P < .001). On consensus reading, the presence of three or more features demonstrated 76% sensitivity, 94% specificity, 94% positive predictive value [PPV], and 80% negative predictive value [NPV] for all DACs and 100% sensitivity, 95% specificity, 81% PPV, and 100% NPV for pure DACs. The DACs and PACs showed no difference in contrast enhancement (100% vs 100%; P >.99, median T2 signal intensity (254 vs 230; P = .99), or apparent diffusion coefficient (median, 677 10-6 mm2/sec vs 685 10-6 mm2/sec; P = .73). Conclusion The presence of intermediate T2 signal, well-defined margin, lobulation, and/or hypointense rim, together with restricted diffusion and contrast enhancement at multiparametric MRI of the prostate, suggests prostatic ductal adenocarcinoma rather than prostatic acinar adenocarcinoma. © RSNA, 2022 Online supplemental material is available for this article.