OBJECTIVE: The objective of this study was to elucidate associations between adiposity reduction and changes in HbA1c and insulin use among adults with type 2 diabetes and overweight or obesity. METHODS: Changes in BMI, waist circumference, and total percent fat mass were obtained over 8 years among 1316 individuals (aged 45-76 years) enrolled in the Look AHEAD (Action for Health in Diabetes) clinical trial of weight loss. Generalized linear models were used to assess relationships between 5% decreases in adiposity measures with glycated hemoglobin (HbA1c) and insulin use over time. RESULTS: A 5% reduction in total percent fat was associated with 0.15% (95% CI: 0.12%-0.18%) lower mean HbA1c. Similarly, 5% reductions in waist circumference and BMI were also associated with slightly lower mean HbA1c: 0.16% (95% CI: 0.13%-0.19%) and 0.13% (95% CI: 0.11%-0.16%), respectively. These reductions were associated with lower odds of insulin use over time, ranging from 21% lower odds for a 5% reduction in percent body fat to 32% lower odds for 5% reductions in waist circumference and BMI. Associations were evident across subgroups defined by sex, diabetes duration, obesity status, and intervention assignment. CONCLUSIONS: Reductions in adiposity are associated with stabilized and slightly lower HbA1c and a marked reduction in the need for insulin therapy. These benefits generalize across clinical subgroups.