Patients with mutations in the death receptor CD95 (Fas/APO-1) frequently develop B-cell lymphoma. However, solid tumors have not been found in the context of defective CD95. This could be due to the fatal autoimmune proliferative disease that develops in the absence of functional CD95 or to a difference in CD95 signaling in lymphoid versus nonlymphoid tissues. To test this we reconstituted mice that harbor a point mutation in the death domain of CD95 (lpr^cg mice), either in one or in both alleles, with bone marrow from wild-type (wt) mice. After a year one third of the lpr^cg/lpr^cg mice developed spontaneous hepatic neoplasms. In contrast only one of the wt/lpr^cg mice and none of the wt mice developed liver cancer. The agonistic anti-CD95 antibody Jo2 induced massive apoptosis in the liver of wt mice but not in the livers of either wt/lpr^cg or lpr^cg/lpr^cg mice. The susceptibility of lpr^cg/lpr^cg mice to liver cancer cannot solely be due to impaired CD95 mediated apoptosis because there was no clear correlation between apoptosis resistance and tumor formation. A gene chip analysis identified genes selectively upregulated in the liver of wt and wt/lpr^cg mice which may protect these mice from developing liver cancer. Our data represent the first case of CD95 protecting from developing a solid cancer.