This work examines the basis for our earlier observation that certain monoclonal antibodies (MAbs) specific for the B-cell-associated C3d/Epstein-Barr virus (EBV) receptor molecule CD21 also react with the surface of some epithelial cells. Of 9 proven anti-CD21 MAbs now examined on frozen sections of human nasopharynx, tonsil and ecto-cervix, only 3 (HB5, anti-B2, AB1) showed staining of stratified epithelium; 2 of these (HB5, anti-B2) also reacted with the surface of epithelial cells freshly dispersed from these sites. The proportion of HB5- and anti-B2-reactive cells in primary epithelial cultures fell to a low but stable level within days of explantation, while almost all permanently established epithelial cell lines, whether SV40 virus-transformed or of malignant origin, were not reactive with either MAb. This contrasts with the pattern of expression of another surface marker also found selectively on cells of the lymphoid and epithelioid lineages, the CDw40 antigen. Staining with CDw40 MAbs on epithelial sections was usually restricted to the basal (proliferating) layer, but the proportion of CDw40-positive cells increased to a relatively high level in normal epithelial cultures; furthermore, most epithelial cell lines expressed this antigen. Immunoprecipitation from the surface of metabolically labelled epithelial cells with the anti-CD21 MAb HB5 yielded a protein of approximate MW 200 kDa, clearly different in size from the 145 kDa CD21 molecule on B cells. This 200 kDa protein was identified on fresh ecto-cervical epithelium, on primary cultures of a laryngeal carcinoma and on one unusual SV40-transformed epithelial cell line. We conclude that stratified human epithelial cells express a 200 kDa surface molecule which is antigenically related to, but not identical with, the CD21 antigen on B cells. It remains to be seen whether this epithelial cell protein can function as an EBV receptor.