Objective: The triglyceride-glucose (TyG) index, a reliable substitute indicator of insulin resistance (IR), is considered an independent risk factor for long-term outcomes in patients with cardiovascular disease. However, studies investigating the association between TyG and atherosclerotic cardiovascular disease (ASCVD) are limited and lack direct evidence. We aim to examine the relationship between the TyG index and ASCVD through a comprehensive cross-sectional study., Methods: Overall, 7212 participants from the 1999-2004 National Health and Nutrition Examination Survey were included. The baseline TyG index was calculated as ln [fasting triglyceride (mg/dL) × fasting blood glucose (mg/dL)/2]. Restricted cubic spline (RCS) regression, univariate logistic regression, and multivariate logistic regression analysis were used to evaluate the association between the TyG index and ASCVD., Results: In the overall population, a multivariate logistic regression analysis showed that the TyG level was not only positively associated with ASCVD [OR (95%CI): 1.29 (1.01,1.64), P =0.042], coronary artery disease (CAD) [OR (95%CI): 1.82(1.33,2.48), P <0.001], and stroke [OR (95%CI): 2.68(1.54,4.69), P =0.002], but also linearly correlated with all three ( P -overall<0.001; P -non-linear >0.05). Although the TyG index was not associated with peripheral arterial disease (PAD) [OR (95%CI): 1.00 (0.73,1.36), P >0.900], it showed a U-shaped correlation with PAD ( P -overall <0.001; P -non-linear= 0.0085), and the risk of PAD was minimized when TyG=8.67. By incorporating the TyG index into the baseline risk model, the accuracy of ASCVD prediction was improved [AUC: baseline risk model, 0.7183 vs. baseline risk model + TyG index, 0.7203, P for comparison=0.034]. The results of the subgroup analysis were consistent with those of the main analysis., Conclusion: The TyG index was independently associated with ASCVD, CAD, and stroke, suggesting that it may serve as a valid indicator for predicting ASCVD in the entire population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Jihong, Xiaojie, He and Yifan.)