The human CD4+ T-cell repertoire of responses to hemagglutinin (HA) of influenza virus A/Beijing/32/92 was examined 3 to 6 months after natural infection by using a panel of 16-mer peptides overlapping by 11 residues. Short-term CD4+ T-cell lines were derived by using full-length HAs of virus A/Beijing/32/92 from 12 unrelated, major histocompatibility complex (MHC) class I and II haplotyped adults with a history of influenza in November and December 1993 and from 6 adults with no history of influenza during the preceding 4 years but who responded to HA. In contrast to recent murine studies, the human CD4+ T-cell repertoire of responses was dominated by the recognition of highly conserved epitopes. The HA2 subunit, widely regarded as nonimmunogenic, induced strong responses in every donor. This resulted in functional cross-reactivity among influenza A viruses. Our study included one pair of unrelated donors expressing identical HLA DRB1 and DQB1 alleles and two pairs of donors sharing low-resolution MHC class II types. These pairs responded to identical peptides; furthermore, clearly identifiable patterns of response were seen in donors sharing single class II haplotypes, irrespective of the presence of other alleles and exposure history. Two conserved regions which induced responses in 17 of 18 donors were identified (residues 295 to 328 and 407 to 442). Possible implications for cross-reactive T-cell vaccines are discussed.