Interleukin (IL)-1 receptor antagonist (IL-1ra) is a naturally occurring inhibitor of IL-1 which binds to IL-1 receptors without generating immunologic responses. Evidence has recently been provided that the balance between the production of IL-1 and IL-1ra might influence the course of immunoinflammatory diseases such as inflammatory bowel diseases, rheumatoid arthritis (RA) and Lyme arthritis. To assess whether endogenous IL-1ra may also have a role on the course of multiple sclerosis (MS) we presently studied the fluctuation of the serum levels of IL-1ra in patients with relapsing remitting (RR) MS either during remission or exacerbation. Moreover, to evaluate whether the beneficial effect of IFN-beta on the course of MS might also be mediated by an increased production of IL-1ra, we measured the levels of circulating IL-1ra in MS patients prior to and after 6 months of continuous treatment with natural human IFN-beta (6,000,000 IU three times a week for 6 months). Our results demonstrated that, relative to control subjects, IL-1ra serum levels are "normal' during remitting phases of RR MS but significantly elevated either during exacerbations or in response to IFN-beta treatment.