BACKGROUND: To explore whether healthy lifestyle factors (HLFs) predict a lower risk of major macrovascular and microvascular events and death in people with type 2 diabetes (T2D) with a high risk of vascular complications. METHODS: Post hoc analyses of 11,133 participants with T2D in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial who were assigned a score ranging from 0 to 4 based on the number of baseline HLFs: never smoked, moderate-to-vigorous physical activity, ideal waist/hip ratio, and low-to-moderate alcohol consumption. Multivariable Cox models were used to determine associations of 0, 1, 2, and ≥ 3 HLFs with vascular events and all-cause mortality. RESULTS: Compared to participants with no HLFs, hazard ratios for participants with 3 or 4 HLFs were 0.68 (95% confidence interval [CI] 0.57-0.81) for the composite of major macrovascular or microvascular events, 0.58 (0.46-0.75) for major macrovascular events, 0.78 (0.61-0.99) for microvascular events, and 0.48 (0.37-0.63) for all-cause mortality during a median follow-up of 5 years. Each increment in HLF score was significantly associated with lower rates of these outcomes. There was no heterogeneity in the effect on any outcome by HLF across randomized intensive blood glucose control and blood pressure lowering treatments. CONCLUSIONS: HLFs are associated with lower risks of major macrovascular and microvascular events and lower rates of death in high-risk adults with T2D.