Multiple sclerosis [MS] is a chronic inflamatory disease of the central nervous system which has been postulated to be a T cell mediated disease. We examined proliferation of mononuclear cells to OKT3 mAb, Con A, ionomycin plus PMA and human myelin basic protein in subjects with relapsing-remitting and chronic progressive multiple sclerosis. Age and sex matched controls demonstrated a good proliferation to anti-CD3 mAb whereas subjects with relapsing-remitting multiple sclerosis showed a significantly decreased anti-CD3 mAb response. There was no difference in mitogen, ionomycin plus PMA or human MBP proliferation between controls and MS subjects. There was also a trend for decreasing anti-CD3 mAb proliferation in patients with chronic progressive multiple sclerosis compared to controls. LPS significantly decreased anti-CD3 mAb proliferation in controls but not in the MS subjects. An abnormality of signal transduction via the CD3 T-cell receptor complex in T cells and responsiveness to the immunomodulatory effect of IFN inducers may exist in multiple sclerosis.