Accumulating evidence indicates an immunosuppressive role for CD4+CD25+ regulatory T cells (Tregs) in autoimmune diseases. Although an impaired Treg function in patients with relapsing-remitting multiple sclerosis (RR-MS) has been reported recently, no information is available so far about Treg function in the progressive stage of the disease. In the present study, the phenotypic and functional characteristics of CD4+CD25+ T cells isolated from the peripheral blood of patients with RR-MS and secondary progressive multiple sclerosis (SP-MS) were investigated. No significant quantitative or phenotypic abnormalities in CD4+CD25+ T cells from RR- and SP-MS patients were detected. However, whereas a reduced suppressor function of CD4+CD25+ T cells toward proliferation and interferon-γ production of CD4+CD25– responder T cells was found in RR-MS patients, SP-MS patients showed a normal Treg function. The suppressive capacity of MS-derived CD4+CD25+ T cells was correlated with disease duration but not with age, indicating that Treg function is more affected in the early phase of the disease process. Consistently with the suppressive capacity, CD4+CD25+ T cells from SP-MS patients showed normal levels of FOXP3 mRNA in contrast to RR-MS patients that had a reduced FOXP3 expression. These data are the first to demonstrate differences in function and FOXP3 expression of CD4+CD25+ T cells from patients with RR- and SP-MS. © 2006 Wiley-Liss, Inc.