Five cases of nodular, lymphocyte predominant Hodgkin's disease (nLP HD), in which an association with (n = 3) and transformation to (n = 2) large cell lymphoma (LCL) were found, were studied with monoclonal antibodies against B-, T-, and Reed-Sternberg (R-S) cell-associated antigens and epithelial membrane antigen (EMA) on paraffin sections. Both lymphocytic (L) and histiocytic (H) cells of nLP HD and lymphoma cells of LCL expressed multiple B-cell-associated antigens (detected by LN-1/CDw75, L26, MB2, DBB.42, DBA.44, DND.53, DNA.7 antibodies) but did not react with antibodies against T-cell-associated (MT1, UCHL1/CD45RO) (one exception for CD45RO in LCL) and R-S cell-associated (Leu-M1/CD15, Ber-H2/CD30) antigens. EMA was expressed by L and H cells in all cases and conserved in LCL cells, emphasizing the frequent expression of EMA by the diagnostic cells of nLP HD. An antibody (BNH9) against blood group-related antigens (H and Y oligosaccharide antigens) that does not normally react with lymphoid cells was found to be reactive with few L and H cells in two of five and most LCL cells in four of five cases. The finding might be indicative of abnormal activation of lymphoid cells. The data reinforce current implications that nLP HD is a B-cell malignancy in evolution and that it is not truly representative of Hodgkin's disease in terms of biological and clinical behavior.