Merkel cell carcinoma (MCC) is recognized by its morphologic features and by its classic immunophenotypic properties. Although MCCs demonstrating nonclassic immunoreactivities have been described, a case documenting a change in immunophenotype during the course of disease progression has not been previously reported. We report a case of MCC that initially demonstrated cytokeratin 20 positivity but lost expression in subsequent metastases. Likewise, thyroid transcription factor-1 was initially negative in the tumor but expression was present in metastatic lesions.