Hodgkin's disease (HD) is an aggressive human lymphoproliferative disease that displays a curious pleomorphic histopathologic appearance unlike that of any of the common non-Hodgkin's lymphomas (NHL). Although the bizarre giant cells of the HD lesion, the Reed-Sternberg cells (RSC) and mononuclear variant Hodgkin's cells (HC), have been considered to be malignant cells, little objective evidence supports this conclusion. We have studied the proliferative characteristics of T cell as well as RSC and HC-enriched populations from HD lesions, and found the majority of the proliferative activity in the T cell populations. RSC-enriched populations not only showed little spontaneous proliferation, but also did not respond to a variety of cytokine growth factors in vitro, suggesting that these cell populations are not actively growing cells. Further molecular studies to identify possible monoclonal T or B cell populations in HD lesions, using a TCR beta chain probe and IgH probes respectively on Southern blot analysis, revealed no evidence of monoclonal lymphoid cell populations. Additional studies on the characteristic T cell immunodeficiency in HD were also undertaken. Our previous studies had associated a decrement in IL-2 production with this defect. Our studies now show that an intrinsic T cell abnormality exists when HD patients' T cells are stimulated with agonistic MAb that can optimally activate and stimulate IL-2 production in normal control T cells.