Objective To evaluate the associations between the serum anion gap (AG) with the severity and prognosis of coronary artery disease (CAD). Methods We measured serum electrolytes in 18,115 CAD patients indicated by coronary angiography. The serum AG was calculated according to the equation: AG = Na+[(mmol/L) + K+ (mmol/L)] - [Cl-(mmol/L) + HCO3(-)(mmol/L)]. Results A total of 4510 (24.9%) participants had their AG levels greater than 16 mmol/L. The serum AG was independently associated with measures of CAD severity, including more severe clinical types of CAD (P < 0.001) and worse cardiac function (P = 0.004). Patients in the 4th quartile of serum AG (>= 15.92 mmol/L) had a 5.171-fold increased risk of 30 days all-cause death (P < 0.001). This association was robust, even after adjustment for age, sex, evaluated glomerular filtration rate [hazard ratio (HR): 4.861, 95% confidence interval (CI): 2.150-10.993, P < 0.001], clinical diagnosis, severity of coronary artery stenosis, cardiac function grades, and other confounders (HR: 3.318, 95% CI: 1.76-2.27, P = 0.009). Conclusion In this large population-based study, our findings reveal a high percentage of increased serum AG in CAD. Higher AG is associated with more severe clinical types of CAD and worse cardiac function. Furthermore, the increased serum AG is an independent, significant, and strong predictor of all-cause mortality. These findings support a role for the serum AG in the risk-stratification of CAD.