Recent literature indicates that females are more resistant to shock, trauma and sepsis-induced immune dysfunction and organ injury than males. Consequently, using trauma-hemorrhagic shock (T/HS) and burn models, we tested whether the neutrophil response to trauma occurred in a sexually dimorphic fashion and the role of sex hormones. Neutrophil activation, as reflected by CD11b expression and respiratory burst activity, was increased to a greater extent in male than female rats after T/HS or burn injury. Testosterone appeared to potentiate neutrophil activation, since castration reduced neutrophil activation, while ovariectomy had little effect. Mechanistically, this sexually-dimorphic neutrophil response appeared to be due to both cellular and humoral factors. Evidence for a cellular difference between male and female neutrophils is based on the observation that naive female neutrophils were more resistant to activation by burn or T/HS plasma and lymph than naive male neutrophils and that this resistance varied over the estrus cycle. Additionally, the humoral environment was more neutrophil activating in male rats, since burn and T/HS plasma and lymph from male rats activated naive male neutrophils to a greater extent than comparable samples from females. Lastly, in vitro experiments examining the effects of estrogen on calcium signaling, it appears that estrogen limits trauma-induced neutrophil activation, at least in part, by limiting the entry of calcium into the cell via SOCE mechanisms. In conclusion, there is a striking sexual dimorphism in neutrophil responses after trauma and these changes reflect both cellular resistance to activation as well as a less activating humoral environment.