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Shan Lin,* Wanmei He,* Zixuan Hu, Lihong Bai, Mian Zeng Department of Medical Intensive Care Unit, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Mian ZengDepartment of Medical Intensive Care Unit, The First Affiliated Hospital, Sun Yat-Sen University, No. 58 Zhongshan Road 2, Guangzhou, Guangdong, 510080, People’s Republic of ChinaEmail zengmian@mail.sysu.edu.cnBackground: Currently, there have been studies showing a correlation between sex differences and prognosis. Nevertheless, the conclusions of clinical studies on sex-based differences are controversial. We aimed to evaluate the effect of sex on the short- and long-term survival of critically ill patients with sepsis.Methods: We use the critical care database of the healthcare information mart. Cox models were conducted to determine the relationship of 28-day and 1-year mortality with a different sex. Interaction and stratified analyses were conducted to test whether the effect of sex differed across age and sequential organ failure assessment (SOFA) score subgroups.Results: A total of 12,321 patients were enrolled in this study. The Cox regression analysis showed that the 28-day and 1-year mortality rates of female patients were significantly lower than those of male patients by 10% and 8%, respectively (hazard ratio [HR]=0.90, 95% confidence interval [CI] 0.83– 0.98, and HR=0.92, 95% CI 0.87– 0.97, respectively). The effects of the association between sex and 28-day and 1-year mortality were broadly consistent for age and the SOFA subgroup variables. Only age was observed to have significant interactions in the 1-year mortality (P=0.0177). Compared with male patients, female patients aged < 50 years had a long-term survival advantage (HR=0.77, 95% CI 0.62– 0.95). In contrast, we did not find sex-based differences in the short- and long-term survival for patients aged ≥ 50 years.Conclusion: In the current retrospective large database review, the 28-day and 1-year mortality were significantly lower in females than in male patients among critically ill patients with sepsis. Notably, there was an interaction between age and sex, and whether female-associated hormones or other contributing factors affect the clinical outcomes of patients with sepsis needs to be further researched.Keywords: critical care, sepsis, sex, prognosis