Prostatic xanthoma may mimic high-grade prostatic adenocarcinoma or prostate cancer treated with hormone therapy. From 1995 to 2006, 40 cases of prostatic xanthoma were diagnosed at The Johns Hopkins Hospital. Thirty-four cases were received in consultation from outside institutions. Hematoxylin and eosin-stained or unstained slides were available in 27 cases (24 consultation cases; 3 in-house cases). Xanthoma was found on needle biopsy in 25 cases, with 2 cases noted on transurethral resection of prostate. Twenty-six cases contained only 1 focus of prostatic xanthoma with 1 case having 3 foci on the same core biopsy specimen. In 21 xanthomas, the lesions were small measuring 1 mm with the largest one measuring 2.5 mm. Xanthoma cells had small uniform, benign-appearing nuclei, small inconspicuous nucleoli, and abundant vacuolated foamy cytoplasm. No mitoses were identified. Focal necrosis was identified in 1 case. Most xanthomas were arranged in circumscribed solid nodular pattern (17 cases). Ten xanthomas consisted of cords and individual cells infiltrating the prostatic stroma, further mimicking high-grade prostate carcinoma. Two xanthomas contained a mixed circumscribed nodular pattern and infiltrating pattern. Of cases with the lesion still present on slides for immunohistochemistry, CD68 was diffusely strongly positive in 18/19 (94.7%) and CAM5.2 was positive in none of the cases 0/14 (0%). One of 15 (6.7%), 2/17 (11.8%), and 1/12 (8.3%) cases were positive for prostate-specific antigen, prostate-specific acid phosphatase, and alpha-methylacyl-CoA racemase, respectively. Careful attention to morphology with adjunctive use of CD68 and CAM5.2 immunohistochemical stains are helpful in the diagnosis of prostatic xanthoma, especially in difficult cases with an infiltrative pattern.