Traumatic brain injury (TBI) is a significant cause of death and disability in the United States. Sex has not been thoroughly examined as a factor that may influence outcome following TBI. Clinical studies involving humans that have focused on sex and TBI outcome have yielded inconclusive results, yet sex-related physiologic differences have been demonstrated in animal studies. The purpose of this study is to examine the interaction of sex and age in relation to outcome at 3 and 6 months postinjury in a population of individuals with TBI. The sample includes 157 subjects (124 males, 33 females), 16 to 89 years of age, admitted to a level 1 trauma center following TBI. Physiologic data and information about injury severity and clinical course were gathered during hospitalization. Outcome was assessed at 3 and 6 months postinjury using the Extended Glasgow Outcome Scale (GOSE) and Functional Status Examination (FSE). In this sample, there was a significant relationship between sex and age with respect to functional outcome at 6 months following TBI, controlling for initial injury severity. Females age 30 years or older had significantly poorer outcome as measured by the GOSE (P = 0.031) and the FSE (P = 0.037) than either males or younger females. There was also a very different rate of recovery, with women age 30 years and older, on average, showing no improvement between 3 and 6 months postinjury. Further study is needed to elucidate the reasons why sex may affect outcome following TBI.