Expression of T-cell antigens by Reed-Sternberg (RS) cells has not been detected in most studies of Hodgkin's disease (HD). The authors employed an improved method of fixation (paraformaldehyde-lysine-periodate), which sharply defined cell borders and revealed T-cell antigens on RS cells in 8 of 30 (27%) cases of HD. Antigen-specific staining was confirmed by immunoelectron microscopy. RS cells expressed T11 (8/8 cases), Leu-3 or T4 (4/8 cases), Leu-4 or T3 (3/8 cases), but not other T-cell specific antigens (Leu-1, T8, T6, 3A1). RS cells were negative for leukocyte common antigen (LCA/T200), in contrast to positive LCA/T200 staining of RS-like cells in T-cell lymphomas. RS cells in all HD cases were positive for Ki-1 and/or Leu-M1 antigens. The percentage of RS cells expressing T-cell antigens was less than 20% (2 cases), 20-50% (3 cases), or greater than 50% (3 cases). This percentage and the specific T-cell antigens expressed varied in tissues from different sites in each of 2 cases. Expression of T-cell antigens by RS cells was found in nodular sclerosis (6 of 20 cases) and mixed cellularity (2 of 5 cases) but not in lymphocyte predominance (2 cases), lymphocyte depletion (1 case), or unclassified types (2 cases). Two cases of nodular sclerosis contained areas of necrosis surrounded by sheets of lacunar cells (syncytial variant of NSHD). Two other cases were associated with cutaneous lymphoma. One of these cases was mixed cellularity HD, which appeared to be confined to the skin. In a second case, tumor cells of similar phenotype (T4+, Ki-1+) were found in skin and lymph nodes of a patient with coexistent mycosis fungoides and HD. These results are consistent with an origin of RS cells from T cells in some cases of nodular sclerosing and mixed cellularity HD. They also suggest that the same cell type, an activated helper T-cell, is involved in the pathogenesis of both skin lesions and lymphadenopathy of some patients with coexistent mycosis fungoides and HD.