The potency of arsenic trioxide (As2O3) as chemotherapeutic agent is under investigation in various clinical trials. As2O3 was shown to be a potent inductor of apoptosis, and several publications describe the involvement of caspases, reduction of mitochondrial membrane potential and modulation of intracellular glutathione level. However, little is known about the involvement of membrane bound cell death receptors. We investigated the role of CD95 and CD95L in As2O3 mediated apoptosis in various lympho-haematopoietic cell lines. Basal CD95-expression did not correlate with sensitivity to As2O3 and incubation with As2O3 did not alter CD95-expression. We therefore chose two CD95 positive cell lines (CCRF-CEM and Jurkat) to analyse a potential activation of this pathway. We were able to induce apoptosis in these CD95 positive cell lines with activating anti-CD95 antibodies and could block induction of apoptosis by inhibitory anti-CD95 antibodies. In contrast we were not able to block As2O3-induced apoptosis by inhibitory anti-CD95 antibodies. We could block additive effects of arsenic trioxide and an apoptosis-inducing anti-CD95 antibody against CD95 to levels of arsenic trioxide alone using an inhibitory anti-CD95 antibody. Thus, our data provide no evidence for a role of the CD95L/CD95 pathway in As2O3-induced apoptosis.