Background: Merkel cell carcinoma (MCC), an aggressive malignancy that has been increasing in incidence, rarely presents with an epidermotropic pattern. Objective: Vie conducted an immunohistochemical evaluation of 6 previously unpublished cases of epidermotropic MCC, focusing particularly on the staining characteristics of epithelial membrane antigen and cytokeratin-20 in the hope of providing insight into the mechanism of epidermotropism in MCC. Methods: This study is a retrospective evaluation using light microscopy and immunohistochemistry. Results: Forty cases of MCC with pathology at Rhode Island Hospital and the Miriam Hospital in Providence, RI, from 1983 through 2009 were reviewed. Following exclusion criteria, 6 patients (5 men, 1 woman) with a mean age of 82.5 years (range, 72-92) demonstrated epidermotropism. Three of 6 patients had MCC of the eyelid. In cases 1, 3, and 6, the perinuclear dot pattern observed with cytokeratin-20 in the epidermotropic MCC cells was less pronounced than the pattern observed in the dermis, and in all 6 of the tumors, the epidermal staining pattern observed with epithelial membrane antigen was not more or less prominent than the staining observed in the dermis. Limitations: The small total number of cases of epidermotropic MCC is a limitation. Conclusion:: The data presented reinforce the differential diagnosis of tumors with an epidermotropic growth pattern and the importance of immunohistochemical staining in the histologic workup of such tumors: squamous cell carcinoma in situ, melanoma, mycosis fungoides, eccrine porocarcinoma, sebaceous carcinoma of the eyelid, mammary and extramammary Paget disease, MCC, and epidermotropic metastases. It is notable that 3 of 6 identified tumors were located on the eyelid; further study of epidermotropic MCC may shed more light on this finding, either as an unusual coincidence or a finding with unexplained significance. (J Am Acad Dermatol 2010:62:463-8.)