BackgroundNumerous epidemiological studies investigating gender-dependent clinical outcomes in sepsis have shown conflicting evidence. This study aimed to investigate the effect of gender on in-hospital mortality due to sepsis according to age group.MethodsThis study used data from the Korean Sepsis Alliance, an ongoing nationwide prospective multicenter cohort from 19 participating hospitals in South Korea. All adult patients diagnosed with sepsis in the emergency departments of the participating hospitals between September 2019 and December 2021 were included in the analysis. Clinical characteristics and outcomes were compared between male and female. Eligible patients were stratified by age into 19–50 years, 50–80 years, and ≥ 80 years old individuals.ResultsDuring the study period, 6442 patients were included in the analysis, and 3650 (56.7%) were male. The adjusted odds ratio (OR) [95% confidence interval (CI)] for in-hospital mortality for male compared with female was 1.15 (95% CI = 1.02–1.29). Interestingly, in the age 19–50 group, the risk of in-hospital mortality for males was significantly lower than that of females [0.57 (95% CI = 0.35–0.93)]. For female, the risk of death remained relatively stable until around age 80 (Pfor linearity = 0.77), while in males, there was a linear increase in the risk of in-hospital death until around age 80 (Pfor linearity < 0.01). Respiratory infection (53.8% vs. 37.4%,p< 0.01) was more common in male, whereas urinary tract infection (14.7% vs. 29.8%,p< 0.01) was more common in female. For respiratory infection, male had significantly lower in-hospital mortality than female in the age 19–50 groups (adjusted OR = 0.29, 95% CI = 0.12–0.69).ConclusionsGender may influence age-associated sepsis outcomes. Further studies are needed to replicate our findings and fully understand the interaction of gender and age on the outcomes of patients with sepsis.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13054-023-04515-5.