Osteopontin (OPN) is a pleiotropic integrin binding protein with functions in cell-mediated immunity, inflammation, tissue repair, and cell survival. Recent studies have shown that OPN may play an important role in the pathogenesis of experimental autoimmune encephalomyelitis and multiple sclerosis (MS). Here, we investigated the plasma levels of OPN in 221 MS patients and 36 healthy controls using an enzyme-linked immunoassay. The MS group comprised of 71 patients with primary and transitional progressive MS (PP/TP-MS), 35 patients with secondary progressive MS (SPMS), and 115 patients with relapsing-remitting MS (RRMS)[46 patients during clinical remission, 26 patients during relapse, and 43 patients treated with interferon-beta (IFNbeta)]. Levels of OPN in plasma were elevated in SPMS patients compared with healthy controls, RRMS patients in remission, and PP/TP-MS patients. Patients with RRMS during relapse presented higher OPN levels than patients with RRMS during clinical remission. When MS patients were classified based on progression of neurological disability, an inverse relation between levels of OPN and disability progression was observed only in patients with relapsing MS. In RRMS patients receiving therapy with IFNbeta, OPN plasma levels were similar to RRMS patients during remission. These findings suggest that OPN is involved in both acute and chronic disease activity, thus expanding the role of OPN in MS pathogenesis suggested by previous studies. Furthermore, the different profiles of OPN levels found in acute relapses and chronic progression and its apparent lack of influence in primary progressive MS phenotypes raise interesting questions on the actual role of OPN in the pathogenesis of MS.