Sex-based outcome differences have been previously studied after thermal injury, with a higher risk of mortality being demonstrated in women. This is opposite to what has been found after traumatic injury. Little is known about the mechanisms and time course of these sex outcome differences after burn injury. A secondary analysis was performed using data from a prospective observational study designed to characterize the genetic and inflammatory response after significant thermal injury (2003-2010). Clinical outcomes were compared across sex (female vs male), and the independent risks associated with sex were determined using logistic regression analysis after controlling for important confounders. Stratified analysis across age and burn severity was performed, whereas Cox hazard survival curves were constructed to determine the time course of any sex differences found. During the time period of the study, 548 patients met inclusion criteria for the cohort study. Men and women were found to be similar in age, TBSA%, inhalation injury, and Acute Physiology and Chronic Health score. Regression analysis revealed that female sex was independently associated with over a 2-fold higher mortality after controlling for important confounders (odds ratio, 2.2; P = .049; 95% confidence interval, 1.01-4.8). The higher independent mortality risk for women was exaggerated and remained significant only in pediatric patients and demonstrated a dose-response relationship with increasing burn size (%TBSA). Survival analysis demonstrated early separation of female and male curves, and a greater independent risk of multiple organ failure was demonstrated in the pediatric cohort. The current results suggest that sex-based outcome differences may be different after thermal injury compared with traumatic injury and that the sex dimorphism may be exaggerated in patients with higher burn size and in those in the pediatric age group, with female sex being associated with poor outcome. These sex-based mortality differences occur early and may be a result of a higher risk of organ failure and early differences in the inflammatory response after burn injury. Further investigation is required to thoroughly characterize the mechanisms responsible for these divergent outcomes.