Costimulatory molecules help determine T cell responses. CD80 (B7-1) and CD86 (B7-2), costimulatory proteins on antigen-presenting cells, bind to CD28 on T cells. When costimulation is coupled with a signal through the T cell receptor (TCR), T cell proliferation and cytokine secretion are induced. However, TCR signaling without CD80/CD86CD28 costimulation causes anergy. During multiple sclerosis (MS) exacerbations, circulating immune cells are activated, Th1 cytokine levels in the blood are elevated, and blood-derived immune cells destroy brain oligodendroglia. In the experimental autoimmune encephalomyelitis model of MS, CD80 on antigen-presenting cells induces Th1 cell responses; CD86 enhances generation of Th2 cells. Variation in CD80 and CD86 expression is likely to influence immune regulation in MS. We demonstrate that the number of circulating CD80(+) lymphocytes is increased significantly during MS exacerbations, but is normal in stable MS. These CD80(+) lymphocytes are predominantly B cells, based on two-color flow cytometry. The number of CD71(+) and HLA-DR+ lymphocytes and monocytes is also increased in active MS. Therapy with IFN beta-1b markedly reduces the number of circulating CD80(+) B cells and increases CD86(+) monocyte number. HLA-DR+, CD71(+), and CD25(+) mononuclear cell numbers are also reduced by therapy. The number of CD80(+) cells may be a useful surrogate marker during IFN-beta therapy, and reduction of CD80-mediated costimulation may be one therapeutic mechanism by which IFN-beta acts in MS.