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In the current study, to elucidate the clinical features of severe malaria, we performed whole-body positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) of Plasmodium coatneyi–infected acute-phase Japanese macaques. The infected monkeys clearly exhibited increase in splenic FDG uptake indicating marked enhancement of glucose metabolism. The standardized uptake values (SUVs) of the spleen in the infected monkeys were significantly higher than those in the uninfected monkey. At autopsy, splenomegaly was clearly present in all infected monkeys, and histopathologic findings included hyperplasia of lymphoid follicles in white pulp, a large number of activated macrophage, and congestion of parasitized red blood cells (PRBCs) and malaria pigments in red pulp. We suggest that increase in splenic glucose uptake may thus be closely related to activation of splenic clearance system against blood-stage malarial parasites.