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Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common human genetic polymorphism. The deficiency protects against malaria but was shown to worsen the clinical course after severe trauma. This study tested whether the deficiency is associated with altered cytokine responses in vitro and in vivo and affects survival after endotoxemia or polymicrobial sepsis (cecal ligation and puncture).Genotyping of animals was carried out using a novel and improved allele-specific polymerase chain reaction assay. Macrophage and splenocyte responses in vitro and ex vivo were compared using gene array analyses and enzyme-linked immunosorbent assays and flow cytometry under both baseline and lipopolysaccharide-stimulated conditions. Endotoxemia- or sepsis-induced mortality was compared under a variety of treatment and resuscitation protocols.Medical school research laboratories.Litter mates of wild-type and G6PD-mutant mice that display a degree of G6PD deficiency similar to that observed in the African-type human deficiency (20% of normal).Lipopolysaccharide in vivo (lipopolysaccharide from Escherichia coli, 10–35 mg/kg body weight intraperitoneally) resulted in greater interleukin-1β, interleukin-6, and interleukin-10 levels in serum and peritoneal lavage in G6PD-deficient mice compared with wild type. Prevailing doses of lipopolysaccharide in vivo increased mortality in G6PD-deficient animals (40–70%) as compared with wild type (5–40%). In contrast, mortality after cecal ligation and puncture–induced sepsis was similar in G6PD-deficient and wild-type animals either in saline-resuscitated or antibiotic-treated animals. Splenic and blood phagocytes from septic G6PD-deficient and wild-type animals displayed attenuated ex vivo lipopolysaccharide responsiveness.This study demonstrates that G6PD deficiency augments cytokine responses after inflammatory challenges. The deficiency is disadvantageous as reflected in increased mortality after hyperinflammation caused by acute endotoxemia. However, the deficiency may not manifest worsened survival after the immunosuppressed condition associated with severe sepsis.