Previous studies suggested that tetanus and diphtheria toxoids (TTD and DTD, respectively) contain 'universal' epitopes for human CD4+ cells(residues 632-651 and 950-969 of TTD and 271-290, 321-350, 351-370, 411- 430, and 431-450 of DTD). To investigate whether CD4+ cells of 100 randomly selected subjects recognized those sequences, the proliferation of CD4+ cell-enriched blood lymphocytes to TTD and DTD and individual synthetic universal epitopes was measured. CD4+ cells of 98 subjects recognized both toxoids, those of I subject only TTD, and those of 1 only DTD. The TTD peptides and DTD peptides 271-290 and 331-350 were recognized by ≥80% of the toxoid-sensitized subjects. The other DTD sequences were recognized by 63%- 71% of subjects. DR-homozygous subjects recognized several universal epitopes less frequently than did DR-heterozygous subjects. The intensity of responses to the epitope peptides correlated with that to TTD or DTD, consistent with recognition of the peptides by CD4+ cells specific for the cognate toxoid.