A retrospective study analyzed the association of the ROX index with clinical outcomes in 23,502 adult patients with sepsis in the intensive care unit. The ROX index is calculated as the ratio of oxygen saturation to respiratory rate. Patients with a higher ROX index (≥ 6.46) had a significantly lower risk of 28-day mortality (HR = 0.33, 95% CI: 0.31–0.35, p < 0.001) even after adjusting for age, sex, and SOFA score. Mortality risk decreased with increasing ROX index until a value of approximately 10.50, where a plateau was reached. The shortest stays in the intensive care unit and in the hospital were observed with a ROX index of 9.56 and 9.29. The ROX index had moderate predictive accuracy for 28-day mortality (AUC = 0.63), which was better than the SOFA score (AUC = 0.59). Subgroup analyzes confirmed consistent results across different clinical and demographic groups.