The Sézary syndrome (SzS) and adult T-cell leukemia (ATL) are malignant proliferations of mature T-lymphocytes that possess distinct functions. Sézary cells function as helper cells, whereas ATL cells are usually suppressor effectors. Although phenotypically similar (CD4+/CD7-/CD8-), these functional differences between the T-cell lymphoproliferative disorders suggest different patterns of cytokine expression. We wished to delineate the cytokine mechanisms potentially underlying the diverse functional characteristics of SzS and ATL. Therefore, we analyzed the expression of interleukins (IL) 2, 4, and 5, γ-interferon, and transforming growth factor β₁ in the highly purified leukemic T-cells from 5 SzS and 5 ATL patients. Decreased mRNA and protein levels of IL-2, γ-interferon, and IL-5 were detected in mitogen-stimulated ATL and SzS cells when compared to similarly cultured normal CD4+ cells. In contrast, IL-4 production was markedly up-regulated in the leukemic cells of 4/5 SzS patients as compared to ATL and normal controls. Finally, fresh ATL cells secreted higher levels of transforming growth factor β₁ into the culture medium than the malignant T-cells from SzS patients. Collectively these results suggest that, similar to the murine CD4-expressing T-cell subsets Th1 and Th2, different cytokine profiles exist in a human population of CD4+ T-cells. Moreover, the distinct patterns of IL-4 and transforming growth factor β₁ expression by SzS and ATL cells, respectively, are most consistent with the functional differences (i.e., helper versus suppressor activity) between these T-cell malignancies and thus may play important roles in the pathogenesis of the paraneoplastic features associated with these two leukemias.