Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. There is increased interferon (IFN)-gamma secretion in MS patients in vitro, and IFN-gamma administration induces exacerbations of disease suggesting a link between IFN-gamma and disease activity. We observed significantly increased IFN-gamma production in the autumn and winter months compared with the spring and summer months in chronic progressive MS, and this increase was linked to endogenous interleukin (IL)-12 production. Increased seasonal IFN-gamma was not observed in normal control subjects, and there were no seasonal changes in IL-10 in progressive MS. These results suggest a potential environmental link between dysregulated IFN-gamma production and MS disease progression and pathogenesis.