The ability of guinea pigs to make immune responses to the random linear copolymer of L-glutamic acid and L-alanine, GA, and to L-glutamic acid and L-tyrosine, GT, is each controlled by a different immune response gene. On the other hand, the random linear terpolymer of L-glutamic acid, L-alanine, and L-tyrosine, GAT, which contains both GA and GT antigenic determinants, is immunogenic in all guinea pigs. After GAT immunization, all animals develop delayed hvpersensitivity and serum antibody specific for GAT. However, only those guinea pigs possessing the GA immune response gene demonstrate cross-reactive delayed hypersensitivity when challenged with GA. In addition, the anti-GAT antisera produced by those animals having the GA gene contain cross-reacting anti-GA antibodies. The sera from guinea pigs lacking the GA gene have no anti-GA antibody activity. Thus, we have demonstrated that a specific immune response gene controlling responsiveness to a "simple" antigen can determine the specificity of both cellular and humoral immune responses to a more complex antigen.