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Background: MSP-1 of Plasmodium falciparum induces strong prohferative T cell responses even in malaria-nonexposed individuals. Epitopes recognized by malaria-nonimmune T cells have not been identified, and immunological mechanisms inducing such T cell responses remain to be uncovered. MSP-1 is a vaccine candidate, and it should be understood whether those epitopes have any roles in MSP-1-mediated protective immunity. The T epitopes-inducing malaria-naive T cell response was analyzed in the hope of understanding the underlying mechanisms. Methods: Human T cell lines and clones reactive to MSP-1 of P. falciparum were established from malaria-nonexposed Japanese donors in vitro, and epitope peptides were identified. Sequences of those epitope peptides were compared to unrelated peptides in the data base. One of those peptides was tested for both binding to HLA-DR molecules and inducing prohferative responses of MSP-1-reactive T cells. Results: There are at least 6 epitopes recognized by malaria-naive T cells under the restriction by HLA-DRBΓ1502 or 0802. Important amino acids for the T cell recognition were identified for an MSP-1 pep-tide. A yeast peptide which shared those residues induced prohferative responses of MSP-1-reactive T cells. Conclusion: We identified T epitopes in the N-terminal region of MSP-1, some of which showed molecular similarities with unrelated environmental antigens, suggesting the presence of cross-reactive T epitopes in MSP-1. Cytokine production in response to those epitopes suggests regulatory functions of those T cells during primary infection with P. falciparum.