Pro- and anti-inflammatory cytokines are thought to participate in the development and regulation of autoimmunity in multiple sclerosis (MS), a demyelinating disease of the central nervous system (CNS). We analysed the percentage of interferon (IFN)-gamma and interleukin (IL)-4-producing cells in the peripheral blood of both active and stable MS patients, and of healthy controls. After short-term stimulation, cytokine-producing cells were intracellularly stained and sorted. Significantly lower percentages of IFN-gamma and IL-4-producing T cells were found in stable MS patients than in controls, and in active than in stable patients. The diminution affected CD4(+) (Th1, Th2) and CD8(+) (Tc1) phenotypes. Tc2 cells were not detected. The Th1/Th2 ratio did not differ in active and stable MS, nor in controls. The fact that Th2 and Tc1 cell percentages were higher in stable than in active MS possibly indicates that these cells play a downmodulating role in the immune response. In contrast, a role in exacerbating the immune response is not attributable to Th1 cells, given their reduction in acute MS. Our data do not support the hypothesis that MS is a Th1/Th2 paradigmatic disease; rather, they suggest that sequestration in the CNS, or activation-induced apoptosis (whether in vivo or in vitro) may explain reduced levels of IFN-gamma and IL-4-producing subsets in the peripheral blood of clinically acute patients.