Background. In areas of unstable malaria transmission, plasma Plasmodium falciparum histidine-rich protein 2 (PfHRP-2) concentrations parallel total parasite biomass and thus infection severity. However, where transmission is more intense, plasma PfHRP-2 might not reliably predict complications and mortality. Methods. As part of a prospective case-control study of severe pediatric illness in Madang, Papua New Guinea, we recruited 220 children aged 6 months to 10 years with severe falciparum malaria, 48 with uncomplicated malaria, and 139 healthy controls. Groups were matched by age, sex, and province of parental birth. Plasma PfHRP-2 levels were quantified by validated immunoassay. Results. Detectable plasma PfHRP-2 concentrations were present in 21 healthy controls (15.1%). Although plasma PfHRP-2 levels were higher in the children with clinical malaria (P