Weight loss is strongly recommended for overweight and obese adults with type 2 diabetes. Unintentional weight loss is associated with increased risk of all-cause mortality, but few studies have examined its association with cardiovascular outcomes in patients with diabetes.To evaluate 2-year weight change and subsequent risk of cardiovascular events and mortality in established type 2 diabetes.ADVANCE was an international, multisite 2x2 factorial trial of intensive glucose control and blood pressure control. We examined 5 categories of 2-year weight change: >10% loss, 4-10% loss, stable (± <4%), 4-10% gain, >10% gain. We used Cox regression with follow-up time starting at 2 years, adjusting for intervention arm, demographics, cardiovascular risk factors, and diabetes medication use from the 2-year visit.Among 10,081 participants with valid weight measurements, average age was 66 years. By the 2-year exam, 4.3% had >10% weight loss, 18.4% had 4-10% weight loss, and 5.3% had >10% weight gain. Over the following 3 years of the trial >10% weight loss was strongly associated with major macrovascular events (HR 1.75, 95% CI: 1.26, 2.44), cardiovascular mortality (HR 2.76, 1.87, 4.09), all-cause mortality (HR 2.79, 2.10, 3.79), but not major microvascular events (HR 0.91, 0.61, 1.36), compared to stable weight. There was no evidence of effect modification by baseline BMI, age, or type of diabetes medication.In the absence of substantial lifestyle changes, weight loss may be a warning sign of poor health meriting further work-up in patients with type 2 diabetes.