To clarify the origin of Hodgkin (H) and Sternberg-Reed (SR) cells, frozen sections of lymph nodes from 25 patients with Hodgkin's disease were immunostained with a large panel of monoclonal antibodies reactive with cells of lymphoid tissue and granulopoiesis. The results showed that (a) H and SR cells are devoid of markers specific to, or characteristic of B cells, macrophages, dendritic reticulum cells, or interdigitating reticulum cells, and (b) the vast majority of H and SR cells contain granulocyte-related antigens detectable with the monoclonal antibodies TU9 and 3C4, but constantly lack other granulocytic cell markers (such as peroxidase and chloroacetate esterase). Monoclonal antibodies raised against a Hodgkin's disease-derived cell line included one, Ki-l, that was found to be selectively reactive with H and SR cells and a minute, but distinct, cell population in normal lymphoid tissue and bone marrow. The latter hitherto unknown cell population appears to be the normal equivalent of H and SR cells.