Locally advanced prostate carcinoma (PCa) can involve adjacent colorectal tissue. In such cases, accurate assignment of primary source may prove difficult. Given the difference in treatment and prognosis between PCa and colorectal carcinoma (CRCa), an accurate diagnosis is crucial. Surgical pathology files were searched for all cases with a diagnosis of PCa on colorectal biopsy between 1987 and 2006. Histologic and clinical data were available in 23 of the 30 found cases. The diagnosis of PCa was made for the first time at the time of the colorectal presentation in 4 men. Three of the 4 underwent colectomy. Among the remaining 19 men with a previously documented diagnosis of PCa, the overall clinical and endoscopic impression still favored a second primary CRCa in 12 patients. The latter was due in part to the chronologically distant prior PCa diagnosis (mean, 6.9 years; range, 2-18 years). None of the colorectal biopsies demonstrated carcinoma in situ or dysplastic colonic mucosa. PCa architecture in the colonic biopsies was that of Gleason score of 9 to 10 in 20 cases and Gleason score of 8 in the remaining 3. Cribriform or microacinar architecture typical of PCa was seen in 6 cases. Immunostains were positive for prostate-specific antigen, P501S (prostein), prostate-specific membrane antigen, and prostate-specific acid phosphatase, in 16 of 20, 9 of 11, 10 of 11, and 10 of 20 cases, respectively. Three cases lacked immunohistochemical evidence of prostatic differentiation. Caudal-type homebox transcription factor 2 (CDX2) and beta-catenin were negative in all tested cases (0/11 for both). Although relatively rare, initial presentation of PCa as a rectal lesion may lead to an erroneous clinical and or histologic impression of CRCa. Because history of prostate cancer is often remote, clinical findings may be misleading. Pathologists should consider the possibility of prostatic origin in poorly differentiated carcinoma encountered on colorectal biopsy when features such as lack of an in situ component, extrinsic pattern of involvement, microacinar or solid architecture, and/or prominent nucleoli, are noted, especially in the absence of nuclear pleomorphism and mitotic activity. Immunohistochemical studies could help establish the diagnosis.