INTRODUCTION: Selenium (Se), a trace element found in soil and groundwater, is necessary for many biological functions, including cerebrovascular health, through selenoprotein formation. However, high concentrations may be harmful. American Indians face elevated cerebrovascular disease rates, which may be associated with other trace elements, such as Se. This cohort study evaluates associations of Se levels with brain health in older American Indians. METHODS: The Strong Heart Study is a longitudinal cohort of American Indians, with comprehensive medical assessments, including trace element exposure assessment. Urinary Se measurements, brain MRIs, and neuropsychological testing were available for 728 participants aged 65-95 at the time of brain MRI. We evaluated associations of urinary Se (divided by urinary creatinine to account for urine dilution) with MRI and neuropsychological tests and adjusted for potential confounders using linear regression models. RESULTS: Increased urinary Se was significantly associated with abnormal sulcal atrophy, ventricular widening, and increased white matter hyperintensity volume but not independent of sociodemographic factors and common vascular co-morbidities. Increased urinary Se was also significantly and independently associated with decreased performance in verbal fluency and processing speed, independent of sociodemographics, vascular co-morbidities, depression, and traumatic brain injury. DISCUSSION: These findings suggest urinary Se levels, particularly those above 50-60 μg Se/g creatinine, are associated with adverse structural brain findings on imaging and diminished cognitive health in older American Indians. This epidemiologic evidence may be useful for public health professionals in evaluating environmental risk, especially within the context of vulnerable populations and high Se intake.