Associations between HLA-DR/DQ phenotypes and immune responses to the circumsporozoite (CS) protein of the human malaria parasite, Plasmodium falciparum, were investigated in Thai adults. The frequency of DR and DQ types did not differ between 15 high antibody responders and 16 antibody non-responders. Initial results which suggested that lymphocyte responses to a CS-derived peptide (R32tet32) might be HLA-DR associated were not confirmed by subsequent extension of the study. Thus, MHC restriction appears not to be a major factor in the frequently observed unresponsiveness of the immune system to the P. falciparum sporozoite. Based on these results, it is expected that MHC restriction will not be a major obstacle to the application of a malaria vaccine in outbred human populations.