CD95/CD95 ligand interactions are critically involved in the negative regulation of peripheral T-cell responses. Here, we report that serum levels of soluble CD95 are significantly elevated in patients with relapsing remitting multiple sclerosis. In a transectional study, CD95 levels did not correlate with clinical disability or lesion formation on magnetic resonance imaging. Longitudinally, Expanded Disability Status Scale changes were associated with high CD95 levels. Interferon-β (IFNβ) treatment led to an initial increase and subsequent decline of serum CD95 levels. Interestingly, patients generating neutralizing antibodies to the drug had significantly higher baseline CD95 levels before IFNβ treatment than those without neutralizing antibodies.