We report a case of a prostatic adenocarcinoma that showed diffuse aberrant p63 expression in the secretory cells and review the literature and differential diagnosis. p63-positive prostatic adenocarcinoma is rare and is typically encountered when working up an atypical focus with basal markers and α-methylacyl coenzyme A racemase. These carcinomas have unusual morphologic features such as atrophic cytoplasm and basaloid morphology. The differential diagnosis includes basal cell hyperplasia and basal cell carcinoma; morphologic features such as the presence of small, infiltrative acini with nuclear atypia, lack of high-molecular-weight cytokeratin expression, and positive α-methylacyl coenzyme A racemase and prostate-specific antigen expression can help distinguish a p63-positive prostatic adenocarcinoma from atypical basal cell proliferations. Current controversies regarding the grading, prognosis, and molecular profile of p63-positive prostatic adenocarcinomas are also discussed.