Poliovirus-specific cellular immune responses were identified in the peripheral blood mononucleocytes of Sabin-immunized human donors by using a proliferation assay. Complement depletion and monoclonal antibody inhibition studies suggest that the effector population is the major histocompatibility complex (MHC) class II-restricted CD4+ T-helper cell. Immune lymphocytes proliferated to polyacrylamide gel purified-capsid proteins VP1, VP2, and VP3 and, in some individuals, to synthetic VP4, indicating the presence of T-cell epitopes in each of these proteins. Using synthetic peptides, T-cell epitopes have been mapped to specific regions in VP1 which lie near previously identified neutralizing antibody recognition sites. Human leukocyte antigen (HLA) typing of the donor individuals indicated that no MHC class II molecule was held in common between all four donor individuals. Thus, the positive responses observed with peptides p182-201 and p244-261 in three of four and four of four donors suggest that these peptides contain epitopes presented by at least two different MHC molecules. Antibody-blocking experiments suggest that an epitope within VP1 residues 244 to 264 is presented by HLA DQ3.