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Hyperchloremia is frequently observed in critically ill patients in the ICU. Our study aimed to examine the association of serum chloride (Cl) levels with hospital mortality in septic ICU patients.Retrospective cohort study.Urban academic medical center ICU.ICU adult patients with severe sepsis or septic shock who had Cl measured on ICU admission were included. Those with baseline estimated glomerular filtration rate less than 15 mL/min/1.73 m2 or chronic dialysis were excluded.None.Of 1,940 patients included in the study, 615 patients (31.7%) had hyperchloremia (Cl ≥ 110 mEq/L) on ICU admission. All-cause hospital mortality was the dependent variable. Cl on ICU admission (Cl0), Cl at 72 hours (Cl72), and delta Cl (ΔCl = Cl72 – Cl0) were the independent variables. Those with Cl0 greater than or equal to 110 mEq/L were older and had higher cumulative fluid balance, base deficit, and Sequential Organ Failure Assessment scores. Multivariate analysis showed that higher Cl72 but not Cl0 was independently associated with hospital mortality in the subgroup of patients with hyperchloremia on ICU admission (adjusted odds ratio for Cl72 per 5 mEq/L increase = 1.27; 95% CI, 1.02–1.59; p = 0.03). For those who were hyperchloremic on ICU admission, every within-subject 5 mEq/L increment in Cl72 was independently associated with hospital mortality (adjusted odds ratio for ΔCl 5 mEq/L = 1.37; 95% CI, 1.11–1.69; p = 0.003).In critically ill septic patients manifesting hyperchloremia (Cl ≥ 110 mEq/L) on ICU admission, higher Cl levels and within-subject worsening hyperchloremia at 72 hours of ICU stay were associated with all-cause hospital mortality. These associations were independent of base deficit, cumulative fluid balance, acute kidney injury, and other critical illness parameters.