The secondary prevention strategy for cardiovascular disease (CVD) does not include anti-inflammatory treatment, which may lead to long-term inflammation in some patients. The aim of this study was to assess the association between inflammatory risk based on the Glasgow Prognostic Score (GPS) and long-term mortality risk in patients with CVD. This study included 3833 patients (≥ 20 years old) with CVD in the National Health and Nutrition Survey from 1999 to 2010 in the United States. The mortality rate was determined by correlation with the National Death Index on December 31, 2019. The GPS consists of the serum C-reactive protein and the serum albumin. The primary outcome was all-cause death, which included cardiac death and non-cardiac death. Cox proportional hazards adjusted for demographic factors and traditional cardiovascular risk factors were used to test the impact of the GPS on mortality. The sensitivity analysis was conducted on subsets within the cohort of patients with CVD, including congestive heart failure, coronary artery disease, angina, heart attack, and stroke. Among 3833 CVD patients with a median follow-up of 9.6 years, 2431 (63.4%) all-cause deaths, 822 (21.4%) cardiac deaths, and 1609 (41.9%) non-cardiac deaths were recorded. After full model adjustment, compared with those of the GPS (0) group, the hazard ratios (HRs) of all-cause death for GPS (1) and GPS (2) were 1.66 (95% confidence interval (CI), 1.48-1.86) and 2.75 (95% CI 2.01-3.75), respectively (P for trend <
0.001). Compared with those of the GPS (0) group, the HRs of cardiac death for the GPS (1) and GPS (2) groups were 1.69 (95% CI 1.39-2.05) and 2.18 (95% CI 1.22-3.91), respectively (P for trend <
0.001). Compared with those of the GPS (0) group, the HRs of non-cardiac death for the GPS (1) and GPS (2) groups were 1.65 (95% CI 1.44-1.89) and 3.05 (95% CI 2.11-4.40), respectively (P for trend <
0.001). The results of the sensitivity analysis were similar to those of the overall cohort. In our analysis of the United States National Database, we discovered that the GPS, a measure of inflammatory risk, was significantly associated with an increased risk of mortality among patients with CVD. Specifically, we observed that patients with a higher GPS had significantly higher risks of all-cause, cardiac, and non-cardiac mortality compared to those with a lower score. These findings suggest that the GPS, comprising easily obtainable biomarkers, could serve as a valuable tool for risk stratification in CVD patients and may contribute to the improvement of patient outcomes.