Peripheral neuroepithelioma (PN) has been underdiagnosed for many years, because of its histologic resemblance to Ewing's sarcoma in most cases, or occasionally to rhabdomyosarcomas (RMS). Lately, we were able to prove the neuroectodermal nature of the small round cell tumor of thoracopulmonary region ("Askin tumor"), a variant of PN, employing immunoperoxidase to detect the presence of the enzyme neuron-specific enolase (NSE) and electron microscopy (EM). In a wider study of small round cell tumors of childhood, we also found that NSE was only present in neuroectodermal tumors and not in Ewing's sarcoma or lymphoma. However, rhabdomyosarcomas (RMS) were also nonspecifically positive for NSE, and therefore, for distinction of RMS from PN, muscle markers and EM are additional diagnostic tools. Here we evaluated the histologic, immunocytochemical, cytochemical and EM features of 15 cases of PN and correlated them with clinical presentation. All tumors were extra-adrenal and occurred in diverse soft tissue and bony sites, in postganglionic locations. All patients were older than these in classic neuroblastoma (NB) and secreted no catecholamines. All tumors were NSE positive and 50% S-100 protein positive. The EM appearance was overall more primitive but the neural characters were established in most cases. Immunofluorescence with monoclonal antibodies showed a specific pattern of staining for PN, distinct from NB and similar, although not identical to Ewing's sarcoma.