Three cross-sectional studies were conducted in a representative cohort of individuals living continuously in an area holoendemic for malaria in Senegal. Plasma from 145 children and adults were tested. The pattern of antimalarial immunoglobulin class (IgM and IgG) and subclass (IgG1 to IgG4) antibody distribution was determined by enzyme-linked immunosorbent assay using a crude blood-stage antigen of Plasmodium falciparum-infected red blood cells. Adults had higher levels of specific antibodies than children, and IgM, IgG2, and IgG3 accounted for the highest difference (2.9, 6.5, and 4.5 times, respectively). Differences in antibody levels were significant for IgG1 to IgG4 between the lowest and the highest transmission season. No particular isotype distribution pattern could be found associated with any given parasitemia level. The relationship between the optical density (OD) values of each isotype and the risk of clinical malaria attack was tested using a Poisson regression model. Only the IgG3 OD increases were found associated with a significantly reduced risk of malaria attack. These seroepidemiologic data suggest that whereas the total IgG-specific activity is not indicative of any given level of protection against malaria, the level of IgG3 was significantly associated with the relative susceptibility to clinical P. falciparum malaria attacks.