Apoptosis is deregulated in active systemic lupus erythematosus and Fas is overexpressed by T cells, although the role of its soluble form (sFas) is unclear. We have explored both the biological significance and structure of sFas in relation to the disease activity. Serum levels of both sFas and sFas-L were correlated with T cell apoptosis in 26 systemic lupus eythematosus patients along with measurement of poly (ADP) ribose polymerase and CK18. In addition, both proliferative rate and change of ploidy were measured in CD3+ cells after treatment with sFas. Both sFas and sFas-L correlated with apoptosis in patients with active systemic lupus eythematosus. Incubation with sFas greatly suppressed proliferation of CD3+ cells from inactive patients and healthy donors, whereas immunoprecipitation revealed both the 48-kDa full-length Fas and the 26-kDa splicing variant in sera from active patients. We postulate that sFas is released to exert a pro-apoptogen effect. It seems possible that the apoptosis program itself includes the shedding/secretion of different forms of Fas to spread a death signal.