We investigated the prevalence and magnitude of naturally acquired humoral immune response to the major merozoite surface protein (MSP-1) in a malaria-endemic population in Papua New Guinea. A prospective longitudinal study in 0.5–15-year-old children was conducted for one year to examine the relationship between acquired immune response to MSP-1 and subsequent susceptibility to clinical disease. The prevalence and concentration of antibodies to both N-(195A) and C-terminal (BVp42) regions of MSP-1 as well as to the parasite-derived MSP-1 increased with age, with the highest prevalence and concentration of antibodies being detected for the parasite-derived MSP-1 molecule and the C-terminal region of MSP-1. As malaria morbidity decreases with age, a significant negative correlation was observed between antibody levels to both 195A and BVp42 and the incidence rate of clinical malaria. When age and past exposure were corrected for, only antibody concentrations against BVp42 and to a lesser extent parasite-derived MSP-1 were significantly associated with protection from clinical malaria and severe parasitemia. The reduction in the incidence rate of clinical malaria observed in individuals with high antibody concentration to MSP-1 may be due to antibodies directed against epitopes within the C-terminal region of MSP-1.