The Tax1 protein of human T cell leukemia/lymphoma virus type I (HTLV-I) has been shown to stimulate the proliferation of human lymphocytes. Here we report that lymphocyte proliferation can be induced at extracellular Tax1 concentrations as low as 25 pM. The proliferative response induced by extracellular Tax1 is accompanied by an activation of endogenous interleukin-2 receptor alpha-chain (IL-2R alpha) expression in human lymphocytes. Functional activation of IL-2R alpha expression in peripheral blood lymphocytes treated with Tax1 was demonstrated using an [125I]IL-2-binding assay. In addition, an enzyme-linked immunosorbent assay demonstrated that soluble IL-2R alpha in the medium of IL-2- and Tax1-treated cells was over 13-fold greater than in the medium of control treated cells. Overexpression of IL-2R alpha is a common clinical feature of some patients with adult T-cell leukemia (ATL) and tropical spastic paraparesis/HTLV-I-associated myopathy (TSP/HAM). The ability of extracellular Tax1 protein to activate expression of IL-2R alpha in both infected and uninfected lymphocytes may contribute to the abnormal lymphocyte proliferation observed in both ATL and TSP/HAM.