Merkel cell carcinoma is an aggressive cutaneous neoplasm that is often difficult to diagnose because of its histologic and immunohistochemical similarity to metastatic oat cell carcinomas and other cutaneous neoplasms. Our purpose was to determine the utility of immunoperoxidase staining of cytokeratin 20 (CK 20), a newly discovered intermediate filament protein, in Merkel cell carcinomas and other cutaneous tumors. Sixty-one tumors were sectioned and stained with antibodies directed at CK 20. The staining of Merkel cell carcinomas was compared with metastatic oat cell carcinomas, lymphomas, squamous cell carcinomas, basal cell carcinomas, melanomas, metastatic carcinoids, spiradenomas, eccrine carcinomas, adenoidcystic carcinoma, sebaceous carcinomas, hidradenomas, sebaceous epitheliomas, trichoblastomas, mixed tumors, and metastatic adenocarcinomas. Nine of 10 Merkel cell carcinomas stained with antibody to CK 20. Two metastatic carcinomas to the skin were also positive. One hidradenoma and one squamous carcinoma exhibited focal staining, but were otherwise negative. All other tumors were nonstaining. Cytokeratin 20 is a sensitive and specific marker for Merkel cell carcinoma and is helpful in distinguishing between Merkel cell carcinoma and other malignant and benign neoplasms.