Available evidence suggests that human T and B cell responses to a major Plasmodium falciparum malaria antigen (Pf155/RESA) in individuals primed by repeated infections are genetically regulated. In the present study we have attempted to establish whether these regulations reflect genetic restrictions imposed on the immune response by class II molecules of the donor's MHC system. T cell activation (proliferation and IFN-gamma release in vitro) and antibody activity (ELISA) were assayed with synthetic peptides corresponding to major Pf155/RESA epitopes. To associate T cell and antibody responses with the donors' MHC class II genotypes, leukocytes from 145 donors living in holo- or hyperendemic regions of Africa (Liberia, Gambia, Madagascar) were used for genomic HLA class II typing of their DRB-DQA and DQB genes by means of restriction fragment length analysis (RFLP). No associations between T cell responses and HLA-DR or -DQ alleles or DRB-DQA-DQB haplotypes were seen among the West Africans even when the donors were divided into high, medium or low responders. This was also true for a small group of HLA class II identical Malagasy donors including three pairs of twins. However, while the T cell responses between the twin pairs varied, those within the pairs were similar. Very similar findings were made with antibodies binding to Pf155/RESA peptides. Our data imply that the impact of MHC class II gene products on specific immune responses to Pf155/RESA epitopes is weak and hard to demonstrate in outbred human populations naturally primed by infection. This may be due to genetic regulations by other, non-HLA class II coded factors superimposed on possible HLA class II restrictions.