Abstract Background There is limited evidence regarding the evaluation of the association between the triglyceride glucose (TyG) index, an indicator of insulin resistance, and the incident risk of cardiovascular disease (CVD). Therefore, we aimed to examine the relationship between the TyG index and CVD incidence in a cohort of Iranian adults. Methods This study was performed in the framework of the Isfahan Cohort Study (ICS). The study population included 5,432 individuals aged ≥ 35 years. CVD events, including acute myocardial infarction (MI), stroke, and unstable angina (UA), were diagnosed by physicians. The TyG index was calculated as Ln [fasting triglycerides (mg/dL) × fasting plasma glucose (mg/dL)/2]. The relationship between the TyG index and CVD events was investigated using Cox regression models. Receiver operating characteristics (ROC) curve analysis was used to determine the best cut-off for the TyG index for predicting CVD outcomes. Results During a median follow-up period of 11.2 years, a total number of 819 CVD, 164 MI, 172 stroke, and 384 UA were recorded. Following adjustment for multiple confounders, elevated TyG levels were associated with a higher risk of CVD (HR = 1.48; 95% CI 1.22–1.79; p