Abstract Background Acute decompensated heart failure (ADHF) can be complicated by electrolyte abnormalities, but the major focus has been concentrated on the clinical significance of serum sodium levels. Objectives This study sought to determine the prognostic significance of serum chloride levels in relation to serum sodium levels in patients with ADHF. Methods We reviewed 1,318 consecutive patients with chronic heart failure admitted for ADHF to the Cleveland Clinic between July 2008 and December 2013. We also validated our findings in an independent ADHF cohort from the University of Pennsylvania (n = 876). Results Admission serum chloride levels during hospitalization for ADHF were independently and inversely associated with long-term mortality (hazard ratio HR per unit change: 0.94; 95% confidence interval CI: 0.92 to 0.95; p < 0.001). After multivariable risk adjustment, admission chloride levels remained independently associated with mortality (HR per unit change: 0.93; 95% CI: 0.90 to 0.97; p < 0.001) in contrast to admission sodium levels, which were no longer significant (p > 0.05). Results were similar in the validation cohort in unadjusted (HR per unit change for mortality risk within 1 year: 0.93; 95% CI: 0.91 to 0.95; p < 0.001) and multivariable risk-adjusted analysis (HR per unit change for mortality risk within 1 year: 0.95; 95% CI: 0.92 to 0.99; p = 0.01). Conclusions These observations in a contemporary advanced ADHF cohort suggest that serum chloride levels at admission are independently and inversely associated with mortality. The prognostic value of serum sodium in ADHF was diminished compared with chloride.