© 2014 by the American Diabetes Association. OBJECTIVE: Longitudinal evidence linking diabetic retinopathy with changes in brain structure and cognition is sparse. We used data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial to determine whether diabetic retinopathy at baseline predicted changes in brain structure or cognition 40 months later. RESEARCH DESIGN AND METHODS: Participants from the ACCORD-MIND and ACCORD-Eye substudies were included in analyses of cognition (n = 1,862) and MRI-derived brain variables (n = 432). Retinopathy was categorized as none,mild nonproliferative, or moderate/severe. Tests of cognition included the Mini-Mental State Examination (MMSE), Digit Symbol Substitution Test (DSST), Rey Auditory Verbal Learning Test, and Stroop test. Primary brain outcomes were gray matter and abnormal white matter volumes. RESULTS: Baseline retinopathy was associated with lower gray matter volume (adjusted means of 470, 466, and 461 cm3 for none, mild, and moderate/severe retinopathy, respectively; P = 0.03). Baseline retinopathy also predicted a greater change in MMSE and DSST scores at 40 months in each retinopathy category (MMSE: -0.20, -0.57, and -0.42, respectively [P = 0.04]; DSST: -1.30, -1.84, and -2.89, respectively [P = 0.01]). CONCLUSIONS: Diabetic retinopathy is associated with future cognitive decline in people with type 2 diabetes. Although diabetic retinopathy is not a perfect proxy for diabetes-related brain and cognitive decline, patients with type 2 diabetes and retinopathy represent a subgroup at higher risk for future cognitive decline.