SummaryBackgroundHyponatremia has prognostic implications in patients with cirrhosis, and thus, has been incorporated in the 2016 MELD‐UNOS update. Changes in serum chloride are commonly perceived as ‘just’ parallel to changes in serum sodium. However, these are less well studied in the context of cirrhosis.AimsTo investigate whether serum chloride independently predicts outcomes in patients with advanced chronic liver disease (ACLD) and stable clinical course or with critical illness.Methods891 patients with ACLD (defined by hepatic venous pressure gradient [HVPG] ≥6 mm Hg) were followed after HVPG measurement between 2003 and 2020 (ACLD cohort). 181 critically ill patients with cirrhosis admitted to the ICU between 2004 and 2007 were recruited for the ICU cohort. Hypo−/hypernatremia (normal: 136–145 mmol/L) and hypo−/hyperchloremia (normal: 98–107 mmol/L) at baseline were assessed.ResultsACLD cohort: 68% of male patients with a median MELD (adjusted for Na) of 11 (9–17) were included (Child‐Pugh‐stages‐A/B/C: 46%/38%/16%) and followed for a median of 60 months. Lower serum chloride (adjusted average HR per mmol/L: 0.965 [95% confidence interval (95% CI): 0.945–0.986], p = 0.001) showed a significant association with hepatic decompensation/liver‐related mortality on multivariable Cox regression analysis adjusted for age, HVPG, albumin and MELD. In line, hypochloremia was significantly associated with hepatic decompensation/liver‐related mortality (adjusted average HR: 1.656 [95% CI:1.267–2.163], p < 0.001).ICU cohort: 70% of patients were male, median MELD was 31(22–39) at ICU admission (92% with Child‐Pugh‐stage‐C). After adjusting for hypo−/hypernatremia, MELD, and blood pH, hypochloremia remained independently associated with ICU‐mortality (aOR Cl: 3.200 [95%CI: 1.209–8.829], p = 0.021).ConclusionHypochloremia is associated with increased mortality in clinically stable and critically ill patients with cirrhosis independently of MELD including serum sodium.