Cutaneous sclerosing epithelial neoplasms are often difficult to diagnose. Though various immunohistochemical markers have proved useful, some cases remain a diagnostic challenge. We aimed to assess the utility of p63 immunohistochemical staining in distinguishing microcystic adnexal carcinoma (MAC) from sclerosing basal cell carcinoma (SBCC) and desmoplastic trichoepithelioma (DTE). Biopsy samples from 20 SBCC, 10 DTE, and 5 MAC were examined after immunohistochemical staining with p63. Although all adnexal tumors examined demonstrated p63 expression, the pattern of staining was strikingly different in MAC when compared with other tumor types. MAC exhibited a scattered pattern with p63-positive cells around the periphery of tumor nests and minimal staining within the center of the tumor islands. This pattern was more pronounced at increased depth of infiltration into the dermis. A robust and consistent diffuse pattern of staining with p63 was observed in all SBCCs and DTEs. We believe this pattern reflects the multidifferentiation pathway of MAC, with eccrine/sebaceous differentiation occurring at deeper levels of the dermis. The different staining patterns of MACs compared with DTEs and SBCCs can thus serve as a useful diagnostic adjunct in difficult lesions.