We examined the incidence of B lymphocyte (HLA-DRw) alloantigens in patients who exhibited elevated antibody titers to native DNA irrespective of their diagnosis. We found a statistically significant (P less than or equal to 0.0001) association between HLA-DRw3 and the presence of antibodies to native DNA not only in patients with a diagnosis of systemic lupus erythematosus but in other patients who did not share that diagnosis. This association supports the existence of a human immune response gene linked to the HLA complex. These data suggest that the hypothesis of an association between HLA and disease operating through disease susceptibility antigens or genes might be invalid and supports an alternative hypothesis, that HLA and disease associations are a manifestation of an immune response gene that controls the production of specific antibodies in any of several disease states.