Genetic control of the immune response linked to the major histocompatibility (H-2) complex in the mouse has been described for synthetic polypeptide antigens and for low doses of native proteins. The phenomenon is well documented(1,2). Extensive screening of intra-H-2 crossover-derived recombinant strains has localized H-2-linked immune response (Ir) genes to the I-immune response region of the H-2 complex (3). For most antigens, Ir genes are autosomal, dominant, and they segregate as single loci. It is not known whether these crossover-defined loci respresent single genes with multiple alleles or clusters of tightly linked genes (4). In 1972, Stimpfling and Durham (5) postulated that two interacting loci within the H-2 complex were required for the response to the alloantigen, H-2.2 (6), and, in 1975, Dorf et. al. (7) observed a responder phenotype in a recombinant derived from two strains which were nonresponders to the synthetic linear terpolymer, L-glutamic acid, L-lysine, L-phenylaline (GLPhe). Analysis of additional recombinants and complementation tests with F(1) hybrids clearly demonstrated that genes in two intra-I-region loci controlled the immune response to GLPhe. Subsequently, requirement for genes mapping in two intra-I-region loci were reported for porcine LDH(B)(8), the alloantigen Thy-1.1 (9), and for the synthetic terpolymers L-glutamic acid, L-lysine, L-tyrosine and L-glutamic acid, L-lysine, L- leucine (6,10). Demonstration that responses to both synthetic polypeptide and native protein antigens can be controlled by genes in two distinct I-region loci prompted speculation that the phenotypic expression of two I-region genes is a general phenomenon which may provide the key for understanding the mechanism of Ir gene function and cellular collaboration in the immune response. Benacerraf and Dorf (10) have shown that Ir gene complementation is often more effective in the cis than in the trans configuration. This concept is further supported by the data reported for GLPhe (10-12) which indicate that both of the complementing genes must be expressed in each of the cell types participating in the interaction. Failure to detect complementation for the majority of antigens under H-2-linked Ir-gene control might be attributed to the limited number of available intra-I- region recombinant strains.