A distinctive immunologic phenotype was demonstrated for the characteristic large atypical cells in skin lesions of 9 patients with lymphomatoid papulosis (LP). Coexpression of Hodgkin's disease (HD)-associated antigen(s) Ki-1, and often Leu-M1, with helper T-cell antigens T11, T4, and T3 and cellular activation antigens Tac, Ia, and T9 was the most common phenotype, observed in 6 of 9 cases. In 2 cases T-cell-specific antigens were not detected, and the phenotype was indistinguishable from Reed-Sternberg (RS) cells of HD. Numerous Ki-1 positive cells and infrequent expression of Leu-1 antigen by large atypical cells in LP cases facilitated the differential diagnosis between LP and mycosis fungoides. A possible transition between small, medium, and large cells expressing only T-cell antigens and large transformed RS-like cells expressing both T-cell and HD-associated antigens was shown by immunoelectron microscopy. These immunologic findings should prove useful for the diagnosis of LP and may help to explain the unexpectedly frequent clinical associations of LP, mycosis fungoides, and HD.