Fifty four clinically stable multiple sclerosis (MS) patients and 54 age- and sex-matched control subjects were HLA-typed, and their responses to herpes simplex, measles, mumps and rubella antigens were examined by the lymphocyte blast transformation test and by serum antibody titrations. Blast transformation response to purified tuberculin (PPD), mitogen phytohaemagglutinin (PHA), pokeweed mitogen (PWN) and concanavalin A (Con A) and spontaneous proliferation of lymphocytes were also studied. MS patients differed from controls by higher antibody levels to measles and rubella viruses and by lower specific blast transformation responses to rubella and measles antigens. When the relative strength of transformation responses was measured, mumps and herpes simplex responses were also lower in MS patients than in controls. In addition, spontaneous lymphocyte proliferation of MS patients in 6-day cultures was lower than that of control lymphocytes. In mitogen stimulations there were no differences between whole groups, but the oldest patients had lower responses to PHA and Con A than their matched controls. The frequency of HLA-Dw2 was 56.6% in MS patients and 32.1% in controls. The patients with and without Dw2 differed from each other only by a lower specific response to PPD in the Dw2-positive group. The immunological response of Dw2-positive controls resembled that of MS patients: low transformation response to viral antigens, low spontaneous proliferation and elevated measles antibodies. This finding supports the function of a genetically determined type of immune responsiveness with low cell-mediated immunity and high levels of certain viral antibodies as one susceptibility factor in multiple sclerosis.