Objective <p>To investigate the relationship between frailty assessed by the HFRS and in-hospital mortality in ICU patients with sepsis.</p> Method <p>A retrospective analysis of septic ICU patients from the MIMIC-IV database assessed frailty through the Hospital Frailty Risk Score (HFRS). Patients were categorized into non-frail (HFRS &lt; 5, n = 4,882), pre-frail (5 ≤ HFRS &lt; 15, n = 3,134), and frail (HFRS ≥ 15, n = 2,575) groups. The primary outcome was in-hospital mortality. Logistic regression combined with restricted cubic splines (RCS) was employed to evaluate the association between HFRS (categorical and continuous) and mortality. Inverse probability weighting (IPW) validated the results, and subgroup analyses explored frailty-mortality correlations in different patient groups.</p> Results <p>A total of 10,591 patients were included, with 4,737 (44.7%) males and median age of 68.9[57.6, 79.6] years. Altogether, 3,024 (28.6%) experienced mortality during hospitalization. Elevated frailty levels were associated with increased in-hospital mortality, consistent across both continuous and categorical HFRS analyses. A linear association between HFRS and mortality risk was indicated by results from RCS. After controlling for potential confounders, both pre-frail and frail statuses were significantly correlated with higher in-hospital mortality risk (pre-frailty, RR = 1.15, 95% CI: [1.06, 1.26], <i>P</i> = 0.002; frailty, RR = 1.29, 95% CI: [1.17, 1.42], <i>P</i> &lt; 0.001). Furthermore, frailty was significantly positively correlated with longer hospital and ICU stays. These findings were confirmed by IPW.</p> Conclusion <p>Elevated frailty assessed via HFRS was associated with an increased risk of in-hospital mortality and prolonged hospital and ICU stays in sepsis.</p>