Conventional histologic examination of Merkel cell tumors may result in misdiagnosis because of the close similarities these tumors bear to either malignant lymphomas or certain undifferentiated carcinomas. The authors have previously reported that neuron-specific enolase (NSE), a specific marker for neuroendocrine cells, is present in normal Merkel cells and can be used as a marker to identify this cell type. In this study, 11 Merkel cell tumors, identified employing electron microscopy, were studied using immunostaining of NSE by the peroxidase-antiperoxidase method. Varying intensities of NSE immunoreactivity were found in the cytoplasm of all the neoplastic cells in the different cases. The uniformly stained cytoplasm formed a small rim surrounding the large, unstained nucleus. Immunostaining of NSE thus provides a simple and reliable method for the differential diagnosis of Merkel cell tumors from other primary skin tumors which, with the exception of some malignant melanomas, have been shown not to contain NSE immunoreactivity.