Fas/Apo-1 (CD95) triggers programmed cell death (PCD) and is involved in immune response control and cell-mediated cytotoxicity. In the autoimmune/lymphoproliferative syndrome (ALPS), inherited loss-of-function mutations of the Fas gene cause nonmalignant lymphoproliferation and autoimmunity. We have recently identified an ALPS-like clinical pattern (named autoimmune lymphoproliferative disease [ALD]) in patients with decreased Fas function, but no Fas gene mutation. They also displayed decreased PCD response to ceramide, triggering a death pathway partially overlapping that used by Fas, which suggests that ALD is caused by downstream alterations of the Fas signaling pathway. Decreased Fas function is also involved in tumor development, because somatic mutations hitting the Fas system may protect neoplastic cells from immune surveillance. This work assessed the inherited component of the ALD defect by evaluating Fas- and ceramide-induced T-cell death in both parents and 4 close relatives of 10 unrelated patients with ALD. Most of them (22 of 24) displayed defective Fas- or ceramide-induced (or both) cell death. Moreover, analysis of the family histories showed that frequencies of autoimmunity and cancer were significantly increased in the paternal and maternal line, respectively. Defective Fas- or ceramide-induced T-cell death was also detected in 9 of 17 autoimmune patients from 7 families displaying more than a single case of autoimmunity within first- or second-degree relatives (multiple autoimmune syndrome [MAS] patients). Autoimmune diseases displayed by ALD and MAS families included several organ-specific and systemic forms. These data suggest that ALD is due to accumulation of several defects in the same subject and that these defects predispose to development of cancer or autoimmune diseases other than ALPS/ALD.