To evaluate systemic T cell activation and reactivity against putative autoantigens in multiple sclerosis (MS), numbers of interleukin-2 (IL-2) secreting cells were determined in peripheral blood of 32 patients with MS, 7 patients with acute aseptic meningitis (AM) and 12 patients with tension headache (TH). Numbers of IL-2 secreting cells were higher in MS patients compared to patients with AM + TH after stimulation with myelin proteolipid protein (PLP), myelin associated glycoprotein (MAG) and myelin oligodendrocyte glycoprotein (MOG), but not after stimulation with myelin basic protein (MBP). In response to MAG, MOG and acetylcholine receptor (AChR) the frequencies of IL-2 secreting cells were higher in patients with MS than TH, while there were no differences between AM and TH to any of the tested antigens. Between patients with MS and AM there was no difference regarding frequency of IL-2 secreting cells in response to any of the tested antigens except MAG to which the response was higher in MS patients. Six of 10 MS patients had IL-2 secreting cells in response to all four myelin antigens (MBP + PLP + MAG + MOG) or to three antigens, while this broad reactivity was not found in any control patient. There was no correlation between numbers of IL-2 secreting cells in MS patients and clinical variables, including exacerbation versus remission, disability and duration of disease. The results suggest that the systemic T cell response in patients with MS is directed to several antigens.