Chloride (Cl⁻) is the major extracellular anion in the body, accompanying sodium (Na⁺), and is primarily derived from dietary sources. Data suggest that increased dietary Cl⁻ intake increases blood pressure, yet paradoxically, higher serum Cl⁻ appears associated with lower mortality and cardiovascular risk. This implies that serum Cl⁻ also reflects risk pathways independent of blood pressure, serum Na⁺, and bicarbonate (HCO₃⁻). We analyzed 12 968 hypertensive individuals followed up for 35 years, using Cox proportional hazards model to test whether baseline serum Cl⁻ was an independent predictor of mortality. To distinguish the effect of Cl⁻ from Na⁺ and HCO₃⁻, we adjusted for these electrolytes and also performed the analysis stratified by Na⁺/HCO₃⁻ and Cl⁻ levels. Generalized estimating equation was used to determine the effect of baseline Cl⁻ on follow-up blood pressure. The total time at risk was 197 101 person-years. The lowest quintile of serum Cl⁻ (<100 mEq/L) was associated with a 20% higher mortality (all-cause, cardiovascular and noncardiovascular) compared with the remainder of the subjects. A 1 mEq/L increase in serum Cl⁻ was associated with a 1.5% (hazard ratio, 0.985; 95% confidence interval, 0.98–0.99) reduction in all-cause mortality, after adjustment for baseline confounding variables and Na⁺, K⁺, and HCO3⁻ levels. The group with Na⁺>135 and Cl⁻>100 had the best survival, and compared with this group, the Na⁺>135 and Cl⁻<100 group had significantly higher mortality (hazard ratio, 1.21; 95% confidence interval, 1.11–1.31). Low, not high Serum Cl⁻ (<100 mEq/L), is associated with greater mortality risk independent of obvious confounders. Further studies are needed to elucidate the relation between Cl⁻ and risk.