AbstractObjectiveLung is often implicated in sepsis, resulting in acute respiratory distress syndrome (ARDS). The alveolar–arterial oxygen gradient [D(A‐a)O2] reflects lung diffusing capacity, which is usually compromised in ARDS. But whether D(A‐a)O2impacts the prognosis of patients with sepsis remains to be explored. Our study aims to investigate the association between D(A‐a)O2and 28‐day mortality in patients with sepsis using a large sample, multicenter Medical Information Mart for Intensive Care (MIMIC)‐IV database.MethodsWe extracted a data of 35 010 patients with sepsis from the retrospective cohort MIMIC‐IV database, by which the independent effects of D(A‐a)O2on 28‐day death risk was investigated, with D(A‐a)O2as being the exposure variable and 28‐day fatality being the outcome variable. Binary logistic regression and a two‐piecewise linear model were employed to explore the relationship between D(A‐a)O2and the 28‐day death risk after confounding factors were optimized including demographic indicators, Charlson comorbidity index (CCI), Sequential Organ Failure Assessment (SOFA) score, drug administration, and vital signs.ResultsA total of 18 933 patients were finally included in our analysis. The patients' average age was 66.67 ± 16.01 years, and the mortality at 28 days was 19.23% (3640/18933). Multivariate analysis demonstrated that each 10‐mmHg rise of D(A‐a)O2was linked with a 3% increase in the probability of death at 28 days either in the unadjusted model or in adjustment for demographic variables (Odds ratio [OR]: 1.03, 95% CI: 1.02 to 1.03). But, each 10 mmHg increase in D(A‐a)O2was associated with a 3% increase of death (OR: 1.03, 95% CI: 1.023 to 1.033) in the case of adjustment for all covariants. Through smoothed curve fitting and generalized summation models, we found that non‐linear relationship existed between D(A‐a)O2and the death at 28‐day, which demonstrated that D(A‐a)O2had no any impacts on the prognosis of patients with sepsis when D(A‐a)O2was less than or equal to 300 mmHg, but once D(A‐a)O2exceeded 300 mmHg, however, every 10 mmHg elevation of D(A‐a)O2is accompanied by a 5% increase of the 28‐day death (OR: 1.05; 95% CI:1.04 to 1.05,p< 0.0001).ConclusionOur findings suggests that D(A‐a)O2is a valuable indicator for the management of sepsis patient, and it is recommended that D(A‐a)O2be maintained less than 300 mmHg as far as possible during sepsis process.