Merkel cell carcinoma needs to be separated from small cell carcinoma metastatic from visceral sites to skin. Pulmonary small cell carcinoma is the most common primary site of small cell carcinoma. We evaluated the immunophenotypic characteristics of 21 Merkel cell carcinomas and 33 small cell carcinomas of lung using thyroid transcription factor-1 and cytokeratin 20. Thyroid transcription factor-1 was 100% specific for the diagnosis of small cell carcinoma of lung associated with a diagnostic sensitivity of 85%. Cytokeratin 20 was present in 95% of Merkel cell carcinomas; however, 33% of small cell carcinoma of lung were also positive. Both antibodies typically demonstrate diffuse and intense staining of their respective tumor cells. We conclude that thyroid transcription factor-1 is a sensitive and specific marker for small cell carcinomas of lung and that a combination of thyroid transcription factor-1 and cytokeratin 20 is indicated to assist in the differentiation of metastatic small cell carcinoma of lung from merkel cell carcinoma.