OBJECTIVE: Previous studies have observed disruptions in brain white and gray matter structure in individuals with type 1 diabetes, and these structural differences have been associated with neurocognitive testing deficiencies. This study investigated the relationship between cerebral cortical thickness reductions and white matter microstructural integrity loss in a group of patients with type 1 diabetes and in healthy control subjects using diffusion tensor imaging (DTI). RESEARCH DESIGN AND METHODS: Twenty-five subjects with type 1 diabetes for at least 15 years and 25 age- and sex-matched control subjects underwent structural T1 and proton-density and DTI on a 3.0 Tesla scanner. Fractional anisotropy measurements were made on major cerebral white matter tracts, and DTI tractography was performed to identify cortical regions with high connectivity to these tracts. RESULTS: Posterior white matter tracts with reduced fractional anisotropy (optic radiations, posterior corona radiata, and the splenium region of the corpus callosum) were found to have high connectivity with a number of posterior cortical regions, including the cuneus, precuneus, fusiform, and posterior parietal cortical regions. A significant reduction in cortical thickness in the diabetic group was observed in the regions with high connectivity to the optic radiations and posterior corona radiata tracts (P < 0.05). CONCLUSIONS: The direct relationship between white and gray matter structural pathology has not been previously demonstrated in subjects with long-standing type 1 diabetes. The relationship between posterior white matter microstructural integrity disruption and lower cortical thickness demonstrated using a novel DTI connectivity technique suggests a common or interrelated pathophysiological mechanism in type 1 diabetes.