An optimal immunohistochemical panel to distinguish poorly differentiated prostate (PCa),from urothelial (UCa) carcinoma was selected from. a panel consisting of prostate-specific antigen. (PSA) and prostatic acid phosphatase (PAP), high-molecular-weight cytokeratin (HMWCK) (clone 34 beta E12), cytokeratin (CK) 7, CK20, p63, and alpha-methylacylcoenzyme A racemase. The pilot group was composed of poorly differentiated UCa (n = 36) and PCa (n = 42). PSA and PAP stained 95% of PCa vs 0% and 11% of UCa cases, respectively. HMWCK and p63 stained 97% and 92% of UCa vs 2% and 0% of PCa cases respectively. CK7/CK20 coexpression was noted in 50% of UCa cases, whereas 86% of PCa cases were negative with both. A panel of PSA, HMWCK, and p63 was optimal for separating 95% PCa (PSA+/HMWCK and/or p63-) v.s 97% UCa (PSA-/HMWCK and/or p63+). This panel was used on 26 diagnostically challenging cases and resolved 81% of cases as UCa vs PCa. The majority of PCa cases retain PSA. Negative PSA with positive HMWCK and/or p63 establishes cc diagnosis of UCa.