Altered expression of the Fas-Fas ligand apoptotic pathway leads to lymphoproliferative and autoimmune diseases. In lpr/lpr mice and children with autoimmune lymphoproliferative syndrome, defective apoptosis is due to Fas mutations. Large granular lymphocyte (LGL) leukemia is a clonal lymphoproliferative disorder associated with rheumatoid arthritis. Leukemic LGLs are resistant to Fas-dependent apoptosis despite expressing high levels of Fas. Such resistance can be overcome by activating leukemic LGLs in vitro, suggesting inhibition of Fas signaling in leukemic cells. We report that sera from patients with LGL leukemia contain high levels of soluble Fas. Ten of these 33 patients with LGL leukemia also had rheumatoid arthritis. Cloning and sequencing revealed expression of multiple Fas messenger RNA variants in leukemic LGL. These Fas variants, including 3 newly described here, encode soluble Fas molecules. Supernatants from cells transfected with these Fas variants blocked Fas-dependent apoptosis of leukemic LGLs. These results suggest that blockade of Fas-signaling by soluble Fas may be a mechanism leading to apoptosis resistance in leukemic LGLs.