Previous studies have shown that the copolymer of glutamic acid and lysine (GL) is nonimmunogenic in all inbred mouse strains. In contrast, the immune responses to the GL-containing terpolymers, poly- (Glu, Lys, Phe), poly-(Glu, Lys, Pro), and poly-(Glu, Lys, Ala), referred to as GLø, GLPro and GLA, respectively, are under H-2-linked immune response gene control. The immune defect in nonresponder mice to GL or GL-containing terpolymers can be bypassed by immunization with covalent conjugates of these antigens on the immunogenic carrier, fowl γ-globulin (FγG). Furthermore, injection of nonresponder mice with 1 to 100 µg of GL-containing polymers specifically decreases their ability to develop anti-GL specific IgM and IgG plaque-forming cell responses to a challenge with polymer-FγG conjugates. This tolerance is antigen specific, since the PFC response to the carrier molecules (FγG) is not affected. Tolerance can be induced as long as 15 days before or as late as 5 days after challenge with the polymer-carrier conjugate. Tolerance can be demonstrated in the early phase of the PFC response and cannot be transferred into normal recipients. In contrast, under identical experimental conditions most GLø responder mouse strains cannot be tolerized by GLø, however, some exceptions were noted. Genes associated with the H-2 complex control this tolerance process. The data suggest that an inverse relationship exists between the amount of T cell helper activity and the ease of tolerization.