The immune responses against the sequential polypeptides; (T-G-A-Gly)n, (T-A-G-Gly)n, (Phe-G-A-Gly)n and (Phe-A-G-Gly)n were studied in inbred guinea pigs and mice. Strain 13 guinea pigs responded to (Phe-G-A-Gly)n and (T-G-A-Gly)n whereas strain 2 guinea pigs responded to (T-A-G-GLY)n and (Phe-A-G-Gly)n. These responses which are linked to MHC, are only against the helical form of the polymers which have conformational determinants. Significant cross reactions at the humoral and T cell levels (PELS) are exhibited with the following reciprocal combinations: (Phe-G-A-Gly)n and (T-G-A-Gly)n; (T-A-G-Gly)n and (Phe-A-G-Gly)n. With mice, the polymers were shown to be T dependent with the following response patterns: mice of H-2b haplotype respond against (T-G-A-Gly)n; those of H-2b, f and r haplotypes respond against (T-A-G-Gly)n. There are no responders against (Phe-G-A-Gly)n and only mice of H-2f respond against (Phe-A-G-Gly)n. "Nonresponders" respond against the MBSA aggregates of all of these polymers. The Ir gene(s) controlling these T cell dependent H-linked responses mapped to the IA subregion. Antibody responses against (T-G-A-Gly) and (T-A-G-Gly) were quite variable, and were most marked in, F1 mice of (responder and nonresponder) and in backcross populations of (F1 x R) and (F1 x NR). However, the T cell proliferative responses performed with nylon wool purified T cells gave clear cut and predictable distinctions between "responders" and nonresponders and linkage with responding haplotype. Hypotheses advanced to explain these findings relate to the poor immunogenicity (antibody) of these polymers, which have a restricted number of repeating determinants, the B cell mitogenic properties of these polymers and the possible involvement of suppressor cells. The specificities of the humoral responses, i.e. cross reactions, were similar to those found in guinea pigs. However, in contrast to the guinea pig studies cross stimulation with structurally related polymers occurred only in those situations where the immunizing and "crossreacting" polymers were both immunogenic in mice of the same haplotype, i.e., (T-A-G-Gly)n and (Phe-A-G-Gly)n in mice of H-2f haplotypes.