Recent studies highlight the central role of skeletal muscle in sepsis-related inflammation and metabolic problems. ICU-acquired weakness, a condition prevalent in 50-75% of sepsis survivors, is associated with persistent muscle weakness that complicates recovery and reduces long-term survival. The pathogenesis of this weakness is complex, likely resulting from factors such as hyperglycemia, immobility, and drug use during ICU care, which exacerbate conditions such as hypercytokine and hyperoxidative states. The underlying mechanisms remain unclear. Males are more susceptible to septic death, which has been linked to enigmatic molecular causes. Skeletal muscle inflammatory responses contribute significantly to sepsis, and emerging evidence suggests that these responses underlie sex differences in septic mortality. Our investigation of four core genotype (FCG) mice with distinct gonadal and chromosomal patterns highlights the remarkable resistance of female XX mice to septic death. Our analysis of septic FCG muscle tissue reveals differential inflammatory pathway activity and specific overexpression of four inflammation-related genes in XX females. In vitro analysis shows that estradiol, but not testosterone, enhances gene expression. Our study highlights the interplay between gonadal and chromosomal differences, sheds light on sex-specific variations in sepsis, and identifies candidate genes that influence these differences.