The Tax protein of Human T-cell leukemia virus type 1 (HTLV-1) is important for the T-cell immortalizing properties of this virus in vitro and is considered to be responsible for the early stages of leukemogenesis in infected hosts. Tax can upregulate expression of TNF-α and TNF-β, as well as potentiate apoptosis in activated T-cells and in serum starved murine fibroblasts. To examine the role of CD95 (APO-1/Fas) and ICE-proteases in Tax-mediated active T-cell death, Jurkat T cells expressing (APO S) or lacking (APO R) cell surface expression of CD95 (APO-1/Fas) were genetically modified to express hormone-inducible HTLV-1 Tax constructs. Hormone-inducible action of Tax alone was sufficient to promote programmed cell death in CD95-expressing Jurkat T-cell clones. In contrast, clones lacking CD95 surface expression were resistant to the antiproliferative action of Tax. Both APO S and APO R clones exhibited Tax-dependent upregulation of CD95 ligand and TNF-α. Blocking experiments suggested that while the apoptotic action of Tax critically required ICE-protease function it was largely independent of cell surface interaction of CD95 ligand or TNF-α with their corresponding receptors. These observations strongly implicate ICE-proteases in Tax-induced T-cell death, and suggest a possible involvement of CD95 in this process.