Basaloid squamous cell carcinoma (BSCC) is a recently recognized variant of squamous cell carcinoma (SCC) with a predilection to occur in the tongue base, hypopharynx, and supraglottic larynx. In smal biopsy specimens, these tumors can be difficult to distinguish from small cell undifferentiated carcinoma (SCUC) and adenoid cystic carcinoma (ACC). Monoclonal antibodies reactive with cytokeratin (AE1/AE3, 34betaE12, Cam 5.2) as well as a variety of other cellular antigens (vimentin, actin, desmin, chromogranin, synaptophysin, CD57, neuron-specific enolase [NSE], and S100) were used in an immunoperoxidase method with paraffin-embedded tissue to phenotypically characterize 23 cases of BSCC, 10 cases of SCUC, and 15 cases of ACC. The neoplastic cells in 22 of the 23 cases of BSCC reacted with the high-molecular-weight cytokeratin antibody 34betaE12, whereas no reactivity was seen in any of the 10 cases of SCUC. This pattern of 34betaE12 reactivity more consistently differentiated BSCC from SCUC than did reactivity with the neuroendocrine markers chromogranin, synaptophysin, CD57, and NSE. These findings show that immunoperoxidase stains performed on paraffin-embedded tissue are potentially useful in establishing a diagnosis of basaloid squamous cell carcinoma.