CD4+ T cell clones were derived from three volunteers who were protected against malaria after immunization with Plasmodium falciparum sporozoites. T cells specific for an epitope, Pf Th/Tc, contained in amino acids 326 to 345 of the circumsporozoite (CS) protein of P. falciparum (NF54) were derived from all three volunteers. DR1-, -4-, -7-, and -9-restricted T cell clones were found to recognize overlapping, but distinct, epitopes within a 20-mer peptide representing the amino acid 326 to 345 sequence. The Pf Th/Tc epitope contains part of the highly conserved region II as well as part of a polymorphic domain of the P. falciparum CS protein. All of the overlapping epitopes within peptide 326-345 contained at least three amino acids of the amino terminus of the conserved region II, in addition to a variable number of amino acids in the polymorphic region. The DR4-, -7-, and -9-restricted but not the DR1-restricted T cell clones recognized variant peptides representing this polymorphic region of the CS protein of P. falciparum isolates from Africa, Asia, and South America.