We have investigated the pattern of acquired immune responses to the major surface protein of Plasmodium falciparum merozoites (gp 190, PfMSP1) in a malaria endemic population in West Africa. A prospective longitudinal study in 3- to 8-year-old children was conducted to examine the relationship between naturally acquired immune responses to PfMSP1 and subsequent susceptibility to malaria infection and clinical disease. A population cross-sectional survey was performed to investigate changes in immune response with age. The prevalence and concentration of antibodies to all regions of the molecule increased with age with the highest prevalence of antibodies being detected against regions of the molecule which are highly conserved between parasite isolates. In vitro lympho-proliferation and interferon-gamma production in response to recombinant proteins representing polymorphic regions of the molecule also increased with age. Interestingly, proliferative responses to some regions of the molecule, including some highly conserved sequences, were highest in young children and decreased markedly with increasing age. Significant associations were observed between antibody and lymphoproliferative responses to proteins from the C terminus of the molecule and resistance to episodes of fever associated with high parasitaemia in partially immune children. In addition, high concentrations of antibodies to a conserved region close to the N terminus of PfMSP1 were also significantly associated with protection.