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The aim of the study was to evaluate splenic glucose metabolism in macrophage activation syndrome (MAS), characterized by overwhelming systemic inflammation. Splenic 18F-fluorodeoxyglucose (FDG) uptake was compared in patients with MAS and sepsis using positron emission tomography/computed tomography (PET/CT).Clinical and FDG-PET/CT findings from patients with MAS and those with culture-proven sepsis were evaluated. The standardized uptake value (SUV) for the spleen and liver were measured. The maximum of the spleen to liver SUV ratio (SLRmax) was calculated as spleen SUVmax/liver SUVmean. The radiological splenic volume was also measured, and splenic metabolic volume (MV) was defined as the total splenic volume with an SLRmean > 1.14. The association between clinical features, laboratory variables, and SLRmax was analyzed.The median SLRmax and splenic MV were significantly higher in patients with MAS (n = 38) than they were in those with sepsis (n = 15) (SLRmax: 1.51 vs 1.09, P = .001; MV: 346.0 vs 154.0, P = .015). Multivariate analyses revealed that SLRmax > 1.31 was useful for discriminating between MAS and sepsis. SLRmax positively correlated with ferritin and lactate dehydrogenase level in MAS. Furthermore, MAS patients with high splenic FDG uptake (SLRmax > 1.72) had higher in-hospital mortality compared to those with moderate to low splenic FDG uptake (P = .013).This study was the first to demonstrate that splenic FDG uptake is significantly elevated in patients with MAS compared to those with sepsis. This may be useful to differentiate between MAS and sepsis, and to predict poor prognosis in patients with MAS.