Although an increased risk of death among female patients suffering thermal injury has been noted, the differential influence of age has received little attention. Because experimental evidence suggests that sex hormones influence the immune response to thermal injury, an age-related sex influence on patient mortality is biologically plausible as the hormone milieu changes with the onset of menopause. The goal of this study was to estimate the association between sex and mortality after thermal injury in a large, population-based sample. The National Trauma Data Bank™ yielded data for more than 6200 burn patients 20 years of age or older. Logistic regression was used to calculate mortality odds ratios (OR) with 95% confidence intervals (CIs) for men relative to women, both overall and by age. Adjustments for age, race, burn etiology, percent body surface area burned, comorbid conditions, and inhalation injury were performed. For the overall study population, the adjusted risk of death was approximately 30% lower for males (OR 0.67, 95% CI 0.52–0.87). Within age strata, the adjusted association was statistically significant only in those aged 20 to 34 years (OR 0.45; 95% CI 0.24–0.87); 35 to 49 years (OR 0.71; 95% CI 0.39–1.30); 50 to 64 years (OR 0.55; 95% CI 0.31–1.00); and 65 years or older (OR 0.85; 95% CI 0.57–1.27). The results of the present study not only indicate that women have an increased odds of mortality after thermal injury but also demonstrate a differential effect of age on the association between sex and mortality. On the basis of the findings of the present study as well as the results of experimental studies, further clinical research is needed to investigate the impact of sex hormones on mortality among burn patients.