Technical Abstract: Overweight and obese individuals are encouraged to lose 5–10% of their body weight to improve cardiovascular disease (CVD) risk, but data supporting this recommendation are limited, particularly for individuals with type 2 diabetes. We conducted an observational analysis of participants in the Look AHEAD (Action For Health in Diabetes) study (n = 5,145, 40.5% male, 37% from ethnic/racial minorities) and examined the association between the magnitude of weight loss and changes in CVD risk factors at 1 year and the odds of meeting predefined criteria for clinically significant improvements in risk factors in individuals with type 2 diabetes. The magnitude of weight loss at 1 year was strongly (P , 0.0001) associated with improvements in glycemia, blood pressure, tryiglycerides, andHDL cholesterol but not with LDL cholesterol (P = 0.79). Compared with weight-stable participants, those who lost 5 to ,10%([means6SD] 7.2562.1 kg) of their body weight had increased odds of achieving a 0.5%point reduction in HbA1c (odds ratio 3.52 [95%CI 2.81–4.40]), a 5-mmHg decrease in diastolic blood pressure (1.48 [1.20–1.82]), a 5-mmHg decrease in systolic blood pressure (1.56 [1.27–1.91]), a 5mg/dL increase inHDL cholesterol (1.69 [1.37–2.07]), and a 40mg/dL decrease in triglycerides (2.20 [1.71–2.83]). The odds of clinically significant improvements in most risk factors were even greater in those who lost 10–15% of their body weight. Modest weight losses of 5 to ,10% were associated with significant improvements in CVD risk factors at 1 year, but larger weight losses had greater benefits.