The study examined a new composite biomarker called the high-sensitivity C-reactive protein to high-density lipoprotein cholesterol (HCHR) ratio to predict 28-day mortality in patients with sepsis. A retrospective cohort study included 1,069 patients with sepsis hospitalized in the intensive care unit between May 2015 and March 2025. The results showed that a higher HCHR value was independently associated with an increased risk of death within 28 days (OR 6.10), with this association being stronger in patients aged 65 years and older and in patients with hypertension. HCHR showed moderate ability to discriminate patients at higher risk of death (AUC 0.686) and outperformed individual markers hs-CRP and HDL-C. The relationship between HCHR and mortality was linear and remained consistent in sensitivity analyses. The authors conclude that HCHR may serve as a useful adjunctive biomarker to support early risk stratification in sepsis as it integrates inflammatory and metabolic information.