Background Triglyceride-glucose (TyG) index is an index to evaluate insulin resistance (IR) and obesity-related metabolic diseases, which is closely related to the high risk of cardiovascular disease (CVD). However, TyG index may be different from the high risk of CVD in middle-aged obese people of different genders. Objective To investigate the relationship between TyG index and the high risk of CVD in middle-aged obese people of different genders, and to evaluate its role in the prevention and treatment of CVD. Methods A total of 30 425 middle-aged obese residents were selected from 10 early screening and comprehensive intervention projects of high-risk CVD population in Anhui Province and investigated by investigators who were trained and qualified, using the preliminary screening questionnaire and basic information registration form designed by the National Cardiovascular Center. The main survey contents included gender, age, hypertension, dyslipidemia, diabetes, smoking and alcohol consumption, etc, and perform a CVD high-risk assessment. The included residents were divided into the male group (n=11 566) and female group (n=18 859). The male group was divided into T1 (7.417-8.870) (n=2 892), T2 (8.871-9.204) (n=2 891), T3 (9.205-9.578) (n=2 892) and T4 (9.579-11.435) (n=2 891) subgroups, the female group was divided into F1 (7.579-8.876) (n=4 715), F2 (8.877-9.183) (n=4 720), F3 (9.184-9.526) (n=4 710) and F4 (9.527-11.647) (n=4 714) subgroups according to the quartiles of TyG index. Binary Logistic regression analysis was used to explore the relationship between TyG index and the high risk of CVD, and Z-test was used to compare the differences in effect values among subgroups. Results The high risk rate of CVD was 28.4% (3 280/11 566) in the male group and 26.0% (4 909/18 859) in the female group. Binary Logistic regression analysis showed that TyG index T2 (F2), T3 (F3), T4 (F4) in male group (female group) were correlated with the high risk of CVD (P