Male sex is more prone to septic death. However, its molecular mechanism remains unknown. Our studies revealed that inflammatory responses in skeletal muscle play a pivotal role in sepsis. Furthermore, recent findings suggested that septic responses in skeletal muscle is a key of the sex differences in septic death. To elucidate if the sex differences in sepsis is from gonadal and sex chromosomal differences, cecal ligation and puncture (CLP)-induced septic symptoms in Four Core Genotypes (FCGs) mice (XX gonadal males or females, and XY gonadal males or females) were investigated in this study. Our survival analysis showed that XX female mice were significantly resistant among FCGs to septic death. Furthermore, our RNA-seq analysis in skeletal muscle of septic FCGs revealed that different activity of inflammatory pathways and four inflammation related genes (Ifi205, Mmp3, Prg4, Saa3) were overexpressed specifically in XX females. In vitro analysis using C2C12 myotubes revealed that estradiol-treatment but not testosterone-treatment enhance mRNA expressions of these genes. Our study suggests the involvement of interactive effects of gonadal and sex chromosomal differences in sex differences in sepsis. Four genes were identified as candidate genes involved in sex difference of sepsis.