We compared healthy blood donors with and without HLA-Dw2 and -Dw3 in immunity assays, the results of which have been found to be abnormal in multiple sclerosis or autoimmune diseases. Tests included lymphocyte blast transformation responses to rubella, mumps and purified tuberculin (PPD), in vitro production of IgG and interferons, natural killer (NK) cell function and measurement of serum antibodies to measles, rubella, mumps and herpes simplex viruses. HLA-Dw2-positive subjects had a lower lymphocyte blast transformation response to rubella virus antigen and a lower NK cell function compared with HLA-Dw2-negative subjects. The presence of HLA-Dw3 was associated with an increased spontaneous and mumps virus-induced immunoglobulin production. No significant differences were found in other assays. These results support the existence of HLA-Dw2- and Dw3-associated deviation of immune responsiveness, which may contribute to the susceptibility of multiple sclerosis or other autoimmune type diseases.