Context: Growing evidence implicates hypothalamic inflammation in the pathogenesis of dietinduced obesity and cognitive dysfunction in rodent models. Few studies have addressed the association between obesity and hypothalamic damage in humans and its relevance. Objective: To determine markers of obesity-associated hypothalamic damage on diffusion tensor imaging (DTI) and to determine whether DTI-metrics are associated with performance on cognitive testing. Design and Participants: This cross-sectional study analyzed DTI-metrics (primary (λ1), secondary (λ2), and tertiary (λ3) eigenvalues; fractional anisotropy (FA); and mean diffusivity (MD)) in the hypothalamus of 24 consecutive middle-aged obese subjects (13 women; 49.8 ± 8.1 years; body mass index [BMI] 43.9 ± 0.92 Kg/m2) and 20 healthy volunteers (10 women; 48.8 ± 9.5 years; BMI 24.3 ± 0.79 Kg/m2). Outcome: measures: Hypothalamic damage assessed by DTI-metrics and cognitive performance evaluated by neuropsychological test-battery. Results: λ1 values in the hypothalamus were significantly lower in obese subjects (P<0.0001). The sensitivity, specificity, and positive and negative predictive values for obesity-associated hypothalamic damage by λ1<1.072 were 75%, 87.5%, 83.3%, and 80.7%, respectively. Patients with hypothalamic λ1<1.072 had higher values of BMI, fat mass, inflammatory markers, carotid-intima media thickness, and hepatic steatosis and lower scores on cognitive tests. Combined BMI and alanine aminotransferase had the strongest association with hypothalamic damage reflected by λ1<1.072 (AUC=0.89). Conclusions: DTI detects obesity-associated hypothalamic damage associated with inflammatory markers and worse cognitive performance. This study highlights the potential utility of λ1 as a surrogate marker of obesity-associated hypothalamic damage