It has been suggested that the malignant cells of Hodgkin’s disease (HD), Reed–Sternberg cells, and their mononuclear variants may be related to cells of the monocyte-histiocyte system. To test this hypothesis, 20 cases of HD were tested with nine antibodies, monoclonal or polyclonal, that normally react with cells of monocytic/histiocytic/granulocytic lineages, as well as PNA, which binds to histiocytes directly. Only two reagents, Leu M1 and PNA bound to the neoplastic cells in 20/22 and 13/22 cases tested, respectively. Leu M1 was the most sensitive reagent and was negative in only two cases of lymphocyte predominant HD. Leu M1 also could be employed in routinely fixed and processed formalin or B5-fixed tissue. This antibody, which was negative in 27 cases of non-Hodgkin’s lymphoma, including 12 peripheral T-cell lymphomas, should prove to be of value in differential diagnosis of HD and morphologically similar reactive and neoplastic lymphoid lesions.