The distinction between primary adnexal carcinoma (PAC) from metastatic breast carcinoma (BrCa) to skin and squamous cell carcinoma (SCC), particularly those with ductal differentiation (SCCDD), can be quite challenging, despite adequate history. The aim of the study was to determine the utility of an immunohistochemistry (IHC) panel to differentiate these entities and apply them to ambiguous tumors. Twenty-seven PAC, 7 metastatic BrCa, 28 SCC, and 16 ambiguous cases (SCCDD vs. PAC, n = 13 and metastatic BrCa vs. PAC, n = 3) were analyzed using CD23, PAX5, D2-40, P63, and CD117 immunohistochemistry. A total of 9 (33%) PAC were CD117 positive, whereas all metastatic BrCa and SCC were negative (P = 0.0002). D2-40 was expressed in 16 (59%) PAC and 16 (57%) SCC cases, but none of the metastatic BrCa cases (P = 0.0041). Of the 13 ambiguous tumors with a differential diagnosis of SCCDD versus PAC, all were positive for P63, 10 were positive for D2-40, and 1 was positive for CD117. Of the 3 ambiguous tumors with a differential diagnosis of PAC versus metastatic BrCA, 2 were positive for CD117, whereas none showed reactivity for D2-40 or P63. All cases were negative for CD23 and PAX5. Our study indicates that CD117 reactivity favors a PAC with a sensitivity and specificity of 33% and 100%, respectively. D2-40 and P63 expression highlighted both PAC and SCC and seems to be useful in excluding metastatic BrCa with a sensitivity and specificity of 58% and 100%, and 98% and 100%, respectively. Despite previous reports, CD23 and PAX5 do not seem to be useful.