BACKGROUND Volatile organic compounds (VOCs) contain hundreds of chemicals and human exposure to VOCs is pervasive. However, most studies have considered only a single chemical or a class of similar chemicals. OBJECTIVE We aimed to investigate the association between urinary volatile organic compound metabolites (mVOCs) and the risk of cardiovascular disease (CVD) in the general population. METHODS The data in this study were collected from the National Health and Nutrition Examination Survey in 2011-2018. Eligible patients were aged ≥20 years for whom complete data for 20 types of urinary mVOCs and CVD outcomes were available. Multivariate logistic regression models were used to elucidate the association between mVOCs and CVD. Generalized additive models were used to examine the nonlinear relationships between mVOCs and CVD. RESULTS 6814 indiviuals were included in the final analysis, of whom 508 had CVD. Higher urinary concentrations of N-acetyl-S-(2-carboxyethyl)-L-cysteine (CEMA) and N-Acetyl-S-(2-cyanoethyl)-l-cysteine (CYMA) and a lower urinary concentration of 2-aminothiazoline-4-carboxylic acid (ATCA) were associated with CVD outcomes after the adjustment for potential confounding factors. A nonlinear relationship and a threshold effect were only observed between N-acetyl-S-(N-methylcarbamoyl)-l-cysteine (AMCC) and CVD among 20 types of mVOCs. There was a significantly positive correlation between AMCC and CVD when AMCC concentration was >2.32 g/mL. CONCLUSIONS The findings of this study suggested a significant correlation between urinary VOC metabolites and CVD. Urinary mVOCs may indicate hazardous exposure or distinct metabolic traits in patients with CVD.