ABSTRACT: BACKGROUND American Indian individuals experience a relatively high risk for cardiovascular disease and have exhibited a higher risk of stroke compared with other racial and ethnic minorities. Although this population has the highest incidence of atrial fibrillation (AF) compared with other groups, the relationship between AF and nonhemorrhagic stroke among American Indian individuals compared with other groups has not been thoroughly studied. METHODS and RESULTS We used the Healthcare Cost and Utilization Project to evaluate risk of nonhemorrhagic stroke among American Indian individuals, with comparisons to White, Black, Hispanic, and Asian individuals, among all adult California residents receiving care in an emergency department, inpatient hospital unit, or ambulatory surgery setting from 2005 to 2011. Of 16 951 579 patients followed for a median 4.1 years, 105 822 (0.6%) were American Indian. After adjusting for age, sex, income level, insurance payer, hypertension, diabetes mellitus, coronary artery disease, congestive heart failure, cardiac surgery, valvular heart disease, chronic kidney disease, smoking, obstructive sleep apnea, pulmonary disease, and alcohol use, American Indian individuals with AF exhibited the highest risk of nonhemorrhagic stroke when compared with either non-American Indian individuals with AF (hazard ratio, 1.38; 95% CI, 1.23-1.55; P<0.0001) or to each race and ethnicity with AF. American Indian individuals also experienced the highest overall risk for stroke, with no evidence that AF disproportionately heightened that risk in interaction analyses. CONCLUSIONS American Indian individuals experienced the highest risk of nonhemorrhagic stroke, whether in the presence or absence of AF. Our findings likely suggest an opportunity to further study, if not immediately address, guideline-adherent anticoagulation prescribing patterns among American Indian individuals with AF.