Outbred Hartley guinea pigs were immunized with the sequential polymer poly(L-Tyr-L-Glu-L-Ala-Gly) (T-G-A-Gly)n, the random copolymer poly(Glu50,Tyr50) (GT), and a low dose of dinitrophenylated guinea pig albumin (DNP-GPA). Only the guinea pigs that carry strain 13 histocompatibility antigen responded to these three antigens as measured by the antigen-binding assay and delayed skin reaction. The immune response (Ir) genes controlling responses to (T-G-A-Gly)n, GT, or DNP-GPA, were found to be distinctive genes. Nonresponder inbred strain 2 guinea pigs were able to produce anti(T-G-A-Gly)n antibodies when immunized with (T-G-A-Gly)n and methylated bovine serum albumin (MBSA) complex, although there was no delayed skin reaction and in vitro cultured lymphocytes did not respond. The in vitro response to (T-G-A-Gly)n of cultured lymphocytes from responder animals was inhibited by strain 2 antistrain 13 alloantisera but not the strain 13 anti-strain 2 alloantisera.