Context: The effects of physiological improvements on cognitive function among persons with type 2 diabetes mellitus (T2DM) are not fully understood. Objective: To determine whether improvements in physiological markers (body weight, blood sugar control, and physical activity) during intensive lifestyle intervention (ILI) are associated with enhancements in cognitive function in older adults with T2DM. Design: Multisite randomized controlled trial. Setting: Academic research centers. Patients or Other Participants: Participants were aged 45-76 years, with T2DM. Intervention: The Action for Health in Diabetes (Look AHEAD) study, a randomized, controlled clinical trial of ILI. Main Outcome Measure: Two to 3 cognitive assessments were collected from 1089 participants, the first and last occurring a mean (standard deviation) of 8.6 (1.0) and 11.5 (0.7) years after enrollment. Results: Greater improvement in blood sugar control was associated with better cognitive scores (fasting glucose and Rey Auditory Verbal Learning Test [AVLT]: P = 0.0148; fasting glucose and Digit Symbol Coding (DSC): P = 0.0360; HbA1C and DSC: P = 0.0477); but weight loss had mixed associations with cognitive scores (greater body mass index [BMI] reduction and worse AVLT overall: P = 0.0053; and greater BMI reduction and better DSC scores among those overweight but not obese at baseline: P = 0.010). Associations were strongest among those who were overweight (not obese) at baseline, and among those with a history of cardiovascular disease (CVD) at baseline. Conclusions: Improvements in glycemic control, but not necessarily weight status, during ILI may be associated with better subsequent cognitive performance. These associations may differ by adiposity and CVD history.