Objective <p>Albumin-corrected anion gap (ACAG) has emerged as a prognostic biomarker for critically ill patients. The mortality risk in patients with chronic kidney disease (CKD) complicated by sepsis is markedly increased Due to immune dysfunction, chronic inflammation, and metabolic disturbances. This study sought to investigate the associations between ACAG levels and mortality outcomes, including ICU, in-hospital, 14-day, 28-day, and 90-day mortality, in critically ill patients with CKD and sepsis.</p> Methods <p>A total of 3459 critically ill patients with CKD and sepsis who were admitted to the ICU at Beth Israel Deaconess Medical Center were included in the analysis. These patients were categorized into two groups—lower and higher ACAG—based on the determined optimal threshold. Multivariate Cox proportional hazards models were employed to examine the associations between ACAG and ICU mortality, in-hospital mortality, as well as 14-, 28-, and 90-day mortality. The receiver operating characteristic (ROC) curve was used to evaluate the predictive ability, sensitivity, specificity, and area under the curve of ACAG for short-term and long-term mortality after admission in this specific patient population. Additionally, restricted cubic spline (RCS) analysis was conducted to explore the potential dose–response relationship between ACAG and these mortality outcomes. Subgroup analyses were conducted to assess how patient characteristics affect the prognostic value of ACAG.</p> Results <p>Compared with the lower ACAG group (n = 2482), the higher ACAG group (n = 977) exhibited significantly higher ICU mortality, in-hospital mortality, and 14-, 28-, and 90-day mortality. Multivariate Cox regression analysis revealed that elevated ACAG levels were independently Linked to a higher risk of ICU mortality, in-hospital mortality, as well as 14-, 28-, and 90-day mortality rates. RCS analysis identified significant Linear relationships between ACAG levels and the risk of ICU death, in-hospital mortality, as well as mortality at 14, 28, and 90&#xa0;days. ROC curve analysis indicated that ACAG had superior predictive ability for prognosis in this patient population compared to anion gap. The results of the subgroup analyses indicated that there were no statistically significant interactions between ACAG and most specific patient subgroup.</p> Conclusion <p>ACAG serves as an independent prognostic marker for critically ill patients suffering from CKD and sepsis. As an easily accessible and cost-effective biomarker, ACAG can aid in the early identification of high-risk patients, optimize patient management, and improve patient outcomes.</p>