Summary: Background: ABO blood type is an inherited trait associated with coagulation factor levels and vascular outcomes. Objectives: To assess the association of blood type with stroke and whether blood type contributes to racial disparities in stroke in the United States. Patients and Methods: The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study recruited 30 239 participants between 2003 and 2007. Using a case-cohort design, blood type was genotyped in 646 participants with stroke and a 1104-participant cohort random sample. Cox models that adjusted for Framingham stroke risk factors were used to assess the association of blood type with stroke. Results: During 5.8 years of follow-up, blood types A or B vs. type O were not associated with stroke. Blood type AB vs. O was associated with an increased risk of stroke (adjusted hazard ratio [HR] 1.83, 95% confidence interval [CI] 1.01-3.30). The association of blood type AB vs. O was greater in those without diabetes (adjusted HR 3.33, 95% CI 1.61-6.88) than those with diabetes (adjusted HR 0.49, 95% CI 0.17-1.44) (P interaction = 0.02). Factor VIII levels accounted for 60% (95% CI 11%-98%) of the association of AB blood type and stroke risk. Conclusion: Blood type AB is associated with an increased risk of stroke that is not attenuated by conventional stroke risk factors, and factor VIII levels were associated with 60% of the association. While blood type AB is rare in the US population, it is a significant stroke risk factor and may play an important role in stroke risk in these individuals. © 2014 International Society on Thrombosis and Haemostasis.