The antibody response of genetically inbred rats to poly(Glu52Lys33Tyr15) is controlled by a complex polygenic system which includes at least two autosomal genes and a sex influence, which may also be genetically determined. The genetic control of the quantity, binding constants, and specificity of the antibody formed linked to the major histocompatibility locus. Factors other than the major genetic ones and the sex influence also affect the quantity of antibody formed, since animals of the same genotype can make significantly different amounts of antibody, depending upon the crosses by which they acquire the major histocompatibility alleles. After immunization with poly(Glu52Lys33Tyr15) the low responders make fewer antibody-producing cells, are not capable of mounting a delayed hypersensitivity reaction to the polypeptide and appear to be deficient in their ability to produce the specific IgM antibody. Immunization of the low responders with antigen aggregated with methylated bovine serum albumin enhances the quantity of antibody formed, increases the binding constants and crossreactivity of the antibody and enhances the delayed hypersensitivity response. In contrast to the findings with the L-amino acid polypeptide, there does not appear to be any genetic control over the antibody response to the D-amino acid enantiomorph poly(DGlu52DLys33DTyr15), which is minimal in all strains.