The cellular origin of the Reed-Sternberg cells of Hodgkin's disease is controversial. The authors studied 14 cases of Hodgkin's disease (nodular sclerosis, 9; mixed cellularity, 3; lymphocyte predominant, 2), utilizing a panel of 16 monoclonal antibodies, including 5 new monoclonal antibodies defining differentiation antigens of the monocyte/macrophage system. Reed-Sternberg cells were found to react with antibodies to Ia-like (HLA-DR) determinants (14 of 14 cases), Leu M1, an antigranulocyte antibody (11 of 14 cases), and rarely B-1, an antibody defining an antigen expressed on human B lymphocytes (2 of 14 cases). Reed-Sternberg cells did not react with any of 5 antibodies to differentiation antigens of the monocyte/macrophage system (MoP9, MoS39, MoR17, MoU26, MoU50). In contrast, reactive histiocytes in the Hodgkin's disease infiltrates stained strongly. The findings are evidence against the monocyte-macrophage origin of Reed-Sternberg cells and support the view that the Reed-Sternberg cells of Hodgkin's disease derive from other cell types, such as interdigitating reticulum cells, or as yet uncharacterized cells which do not share antigens of the monocyte/macrophage system.