Background: The triglyceride glucose (TyG) index is an easily accessible surrogate marker of insulin resistance, an important pathway in the development of type 2 diabetes and cardiovascular diseases. However, the association of the TyG index with cardiovascular diseases and mortality has mainly been investigated in Asia, with few data available from other regions of the world. We assessed the association of insulin resistance (as determined by the TyG index) with mortality and cardiovascular diseases in individuals from five continents at different levels of economic development, living in urban or rural areas. We also examined whether the associations differed according to the country's economical development. Methods: We used the TyG index as a surrogate measure for insulin resistance. Fasting triglycerides and fasting plasma glucose were measured at the baseline visit in 141 243 individuals aged 35–70 years from 22 countries in the Prospective Urban Rural Epidemiology (PURE) study. The TyG index was calculated as Ln (fasting triglycerides [mg/dL] x fasting plasma glucose [mg/dL]/2). We calculated hazard ratios (HRs) using a multivariable Cox frailty model with random effects to test the associations between the TyG index and risk of cardiovascular diseases and mortality. The primary outcome of this analysis was the composite of mortality or major cardiovascular events (defined as death from cardiovascular causes, and non-fatal myocardial infarction, or stroke). Secondary outcomes were non-cardiovascular mortality, cardiovascular mortality, all myocardial infarctions, stroke, and incident diabetes. We also did subgroup analyses to examine the magnitude of associations between insulin resistance (ie, the TyG index) and outcome events according to the income level of the countries. Findings: During a median follow-up of 13·2 years (IQR 11·9–14·6), we recorded 6345 composite cardiovascular diseases events, 2030 cardiovascular deaths, 3038 cases of myocardial infarction, 3291 cases of stroke, and 5191 incident cases of type 2 diabetes. After adjusting for all other variables, the risk of developing cardiovascular diseases increased across tertiles of the baseline TyG index. Compared with the lowest tertile of the TyG index, the highest tertile (tertile 3) was associated with a greater incidence of the composite outcome (HR 1·21; 95% CI 1·13–1·30), myocardial infarction (1·24; 1·12–1·38), stroke (1·16; 1·05–1·28), and incident type 2 diabetes (1·99; 1·82–2·16). No significant association of the TyG index was seen with non-cardiovascular mortality. In low-income countries (LICs) and middle-income countries (MICs), the highest tertile of the TyG index was associated with increased hazards for the composite outcome (LICs: HR 1·31; 95% CI 1·12–1·54; MICs: 1·20; 1·11–1·31; pinteraction=0·01), cardiovascular mortality (LICs: 1·44; 1·15–1·80; pinteraction=0·01), myocardial infarction (LICs: 1·29; 1·06–1·56; MICs: 1·26; 1·10–1·45; pinteraction=0·08), stroke (LICs: 1·35; 1·02–1·78; MICs: 1·17; 1·05–1·30; pinteraction=0·19), and incident diabetes (LICs: 1·64; 1·38–1·94; MICs: 2·68; 2·40–2·99; pinteraction <0·0001). In contrast, in high-income countries, higher TyG index tertiles were only associated with an increased hazard of incident diabetes (2·95; 2·25–3·87; pinteraction <0·0001), but not of cardiovascular diseases or mortality. Interpretation: The TyG index is significantly associated with future cardiovascular mortality, myocardial infarction, stroke, and type 2 diabetes, suggesting that insulin resistance plays a promoting role in the pathogenesis of cardiovascular and metabolic diseases. Potentially, the association between the TyG index and the higher risk of cardiovascular diseases and type 2 diabetes in LICs and MICs might be explained by an increased vulnerability of these populations to the presence of insulin resistance. Funding: Full funding sources are listed at the end of the paper (see Acknowledgments).