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Head and neck carcinomas with basaloid features can be diagnostically challenging. A common diagnostic issue is the distinction between a basaloid squamous cell carcinoma (bSCC) and a basal cell carcinoma (BCC) of cutaneous origin. This is particularly true in small biopsy specimens where classic architectural and histologic features may be difficult to appreciate. A specific diagnosis is essential because of significant differences in clinical outcome and therapeutic management. Ten resection cases of bSCC and BCC of the head and neck were selected based on primary location and the classic morphologic features that characterize these 2 entities. The following immunohistochemical markers were evaluated: epithelial membrane antigen (EMA), Ber-EP4, CD44, Bcl2, androgen receptor, SOX2, and p16. The strongest statistically significant differences in staining patterns were for EMA, p16, and SOX2. EMA was positive in all bSCCs and negative in all BCCs. SOX2 was positive in all bSCCs and in only 3 out of 10 BCCs. Staining was weak and peripheral in the SOX2-positive BCCs. p16 was positive in 8 out of 10 bSCCs and negative in all BCCs. We conclude that bSCC and BCC of the head and neck can be readily distinguished by a limited panel consisting primarily of EMA, and supported by SOX2 and p16.