Analysis of specific IgE responses to highly purified allergens provides a particularly good model to study the genetics of human immune response. The use of this model is illustrated by studies of large populations of allergic individuals in terms of their HLA phenotype, basal total IgE level and specific IgE-mediated sensitivities to rye grass group I (Rye I) and to ragweed Ra3. We find significant associations between HLA-B8 and Rye I response and HLA-A2 and Ra3 response, which become more striking in those atypical allergic subjects who have low total IgE levels. Our studies point to the importance of genetic regulation of basal IgE level in determining specific IgE response. Also, they suggest possible approaches toward a tentative 'mapping' of postulated Ir genes based on the linkage disequilibrium existing within the HLA complex.