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An important and persistent laboratory finding has been that males and females respond differently after traumatic injury and hemorrhagic shock. We have previously presented clinical data showing that male gender is independently associated with a 40% higher rate of multiple organ failure (MOF) and a 25% higher rate of nosocomial infection (NI) after injury; however, the mechanism responsible for this dimorphic response after injury has not been adequately characterized clinically.Data were obtained from a multicenter prospective cohort study evaluating clinical outcomes in severely injured adults with blunt hemorrhagic shock. Proteomic analysis of serum inflammatory cytokines, on days 0, 1, and 4 postinjury, was performed on 46 males and 34 females. Repeated measures ANOVA were used to compare serial IL-1β, TNF-α, IL-6, IL-8, and IL-10 serum levels across gender, while controlling for important confounders. Logistic regression modeling was then used to analyze the independent risk of MOF and NI associated with gender.IL-6 serum levels were statistically higher in males relative to females (p = 0.008). This higher level of IL-6 expression in males remained statistically significant over time even after controlling for differences in age, initial base deficit, ISS, and 12-hour blood transfusion requirements (p = 0.025). No differences in IL-1β serum levels (p = 0.543), TNF-α, (p = 0.200) IL-8 (p = 0.107), and IL-10 (p = 0.157) were found. Males had a higher crude incidence of MOF and an 11-fold higher independent risk of MOF.Persistently elevated IL-6 levels in males are associated with a higher rate of MOF. It is not known if this excessive IL-6 expression in males is causal or only a marker for poor outcome. Further studies are required to elucidate if this early, persistent IL-6 expression is responsible for the gender-based differential outcomes after injury.