OBJECTIVE: The triglyceride-glucose (TyG) index, a reliable surrogate marker of insulin resistance, has been shown as an independent risk factor for stroke. Still, the interaction between metabolic syndrome (MetS) and the TyG index in determining stroke risk remains to be clarified, which may help optimize stroke prevention strategies. This study aims to explore whether metabolic syndrome (MetS) influences the association between the TyG index and the risk of stroke. METHODS: A total of 7770 middle-aged and older participants free of stroke at baseline were enrolled from the China Health and Retirement Longitudinal Study. The TyG index was calculated as ln (triglyceride [mg/dL] × fasting glucose [mg/dL]/2). MetS was defined following the modified International Diabetes Federation criteria. The outcome was self-reported, physician-diagnosed, incident stroke during follow-up. Cox proportional hazard models were used to examine whether MetS influences the associations between the TyG index and the risk of incident stroke. RESULTS: A total of 568 (7.3%) incident stroke cases occurred after a median observation time of 7.0 years. After adjusting for potential confounders, a higher TyG level was associated with an increased risk of incident stroke (hazard ratio (HR) 1.19, 95% CI 1.05-1.33, P = 0.016). The association was significant in participants without MetS (HR 1.69, 95% CI 1.40-1.97, P <
0.001), but not in those with MetS (HR 1.05, 95% CI 0.88-1.21, P = 0.599). The interaction between the TyG index and MetS on the risk of incident stroke was significant (P = 0.004). CONCLUSION: MetS influenced the association of the TyG index with the risk of incident stroke among middle-aged and older Chinese adults. The TyG index may be more effective for stroke risk stratification in populations without MetS compared to those with MetS.