Context. - Poorly differentiated carcinoma on prostate or colorectal biopsy can occasionally present a diagnostic challenge in determining tumor source especially in locally advanced colorectal carcinoma (CRCa) or prostate carcinoma (PCa). Such determination can affect prognosis and therapy. Objective. - To evaluate the role of morphology and immunohistochemistry in the previously mentioned setting. Design. - Surgical pathology and consultation records. Hematoxylin-eosin sections were reviewed in 16 cases (11 PCa, 5 CRCa). Immunohistochemistry for 9 markers was performed in 15 cases. Results. - Dirty necrosis, seen in 5 (100%) of 5 CRCa and 2 (18%) of 11 PCa cases, and the presence of columnar cells with basal nuclei, seen in 5 (100%) of 5 CRCa and 1 (9%) of 11 PCa cases, appear to be the most useful morphologic parameters. Immunohistochemistry confirmed the value of prostate-specific antigen (PSA), CDX2, cytokeratin (CK) 20, and β-catenin in the differential of CRCa (0% PSA+, 60% CDX2+, 80% CK20+, and 100% β-catenin+) versus PCa (80% PSA+, 0% CDX2 +, 10% CK20+, and 0% β-catenin+). P501S had a similar sensitivity as PSA in detecting PCa (80%). Two (20%) of 10 PCa cases were positive for 1 of the 2 markers but not the other. P501S was negative in all 5 cases of CRCa. Conclusions. - P501S is a useful marker in this setting when included together with PSA, CDX2, CK20, and β-catenin. P501S labels a subset of PCa cases that are negative for PSA. Dirty necrosis and/or columnar cells with basal nuclei could also be of help.