This is a retrospective analysis of poorly-differentiated head and neck malignancies at University College Hospital, Ibadan. Eighty-six poorly-differentiated neoplasms were categorized as carcinomas, sarcomas, lymphomas or neuroendocrine cancers with a panel of 7 antibodies (cytokeratin AE1/AE3, vimentin, desmin, myogenin, leukocyte common antigen and neuron-specific enolase). Immunohistochemical and original hematoxylin-eosin diagnoses were contrasted.The male: female ratio was 2.5:1, with mean age of 38.9 years. Nasopharynx, nose and maxillofacial bones were the most common locations. Immunohistochemistry confirmed 54.8% of carcinomas, 70.6% of sarcomas and 80% of lymphomas.Hematoxylin-eosin was able to distinguish between sarcoma and lymphoma but differentiation between a carcinoma and neuroendocrine lesion was poor. Further studies are required to maximize the role of immunohistochemistry as an ancillary diagnostic tool in the West African sub-region.