The transactivator protein of human T-lymphotropic virus I (HTLV-I), Tax, has been associated with the up-regulation of several host cell genes, including interleukin 2 (IL-2), the IL-2 receptor-α(IL-2Rα) chain (CD25), interferon γ(IFN-γ), and tumor necrosis factor (TNF). It has been proposed that an IL-2/CD25 autocrine loop plays a part in maintaining the very high proviral loads often found in HTLV-I infection. Furthermore, abnormal production of inflammatory cytokines might contribute to the pathogenesis of the inflammatory diseases associated with HTLV-I infection. However, there has been no study of the expression of these genes in freshly isolated peripheral blood mononuclear cells (PBMCs) naturally infected with HTLV-I. In the present study, flow cytometry was used to determine which cytokines are produced by freshly isolated PBMCs that spontaneously express the HTLV-I Tax protein. Surprisingly, the results show that intracellular Tax expression is associated with rapid up-regulation of IFN-γ but not TNF or IL-2. A proportion of HTLV-I–infected cells express both IFN-γ and the surface markers of effector memory cells. Such cells are capable of migration through peripheral tissues and could therefore contribute to the inflammation seen in diseases such as HTLV-I–associated myelopathy/tropical spastic paraparesis.