Using monoclonal antibodies to leukocyte common antigen, granulocyte-related antigen, and B-cell specific antigens, L&H variants of Reed-Sternberg (R-S) cells in Hodgkin's disease, lymphocyte predominance type (nodular), exhibited a unique staining profile as compared with R-S cells of other histologic types. L&H variants were strongly immunoreactive for leukocyte common antigen, as defined by monoclonal antibodies PD6/27 and 2B11; whereas other types of R-S cells were negative or rarely positive. R-S cells and variants in 69 cases of Hodgkin's disease of nodular sclerosis (41), mixed cellularity (25) or lymphocyte depletion (3) types, were consistently strongly immunoreactive for Leu-M1, a granulocyte-related antigen, while L&H variants were uniformly nonreactive (4 cases). B-cell specific antigens, detected by three pan-B-cell monoclonal antibodies, were observed only for L&H variants. These observations suggest that L&H variants of R-S cells represent a distinct type of transformed cell, possibly of B-cell origin, and do not share a common lineage with other types of R-S cells. These studies provide further evidence that Hodgkin's disease, lymphocyte predominance type, nodular, may represent a distinct entity.