Background: Serum chloride levels and the advanced lung cancer inflammation index (ALI) score are independent prognostic factors in patients with heart failure (HF). Nevertheless, the interactive relationship between serum chloride levels and the ALI score in predicting all-cause mortality among individuals with acute decompensated heart failure (ADHF) remains undefined. Methods: The study recruited 1221 patients with ADHF who were hospitalized at the University Affiliated Hospital in China between January 2017 and October 2021. The ALI score was calculated as body mass index x serum albumin level/neutrophil-lymphocyte ratio (NLR), which was used to assess inflammation and nutritional status in ADHF patients. Results: Following adjustment for confounders including age, sex, New York Heart Association (NYHA) functional classification, left ventricular ejection fraction (LVEF), log-transformed brain natriuretic peptide (lgBNP), and C-reactive protein (CRP) levels, the independent association of ALI score (hazard ratio (HR): 0.984, 95% confidence interval (CI): 0.977-0.990; p < 0.0001) and serum chloride (HR: 0.915, 95% CI: 0.897-0.933; p < 0.0001) with all-cause mortality persisted. Stratified analysis by ALI score and serum chloride subgroups revealed significant differences in cumulative survival, where lower ALI scores and serum chloride concentrations were associated with a higher risk of all-cause mortality (p < 0.0001).Conclusions: Combining the ALI score with serial serum chloride monitoring adds significant value in predicting all-cause mortality in ADHF patients who may benefit from aggressive chloride correction and anti-inflammatory therapies, potentially modifying the disease trajectory.