INTRODUCTION: Recent literature suggests blood pressure variability (BPV) is an independent risk factor for cardiovascular disease (CVD). Ours is the first study to assess the prognostic value of the intraindividual SD of systolic blood pressure (SBPSD) and diastolic blood pressure (DBPSD) in American Indians. METHODS: We computed BPV for 3,352 American Indians who had 8 nonurgent visit-to-visit blood pressure checks according to their electronic health records, and linked those measurements with Strong Heart Study cohort data. We used Cox proportional hazards models to determine whether the risk of all-cause mortality, CVD mortality, or major adverse cardiovascular events (MACE), was different for SBPSD and DBPSD quartiles, while controlling for covariates. RESULTS: Mean participant age was 54.5 years (SD = 17.3), 66% were female, mean SBPSD was 13.47 (SD = 5.71), and mean DBPSD was 8.05 (SD = 3.02). Over the 20-year follow-up, 45.4% died, 14.6% experienced CVD-related mortality, and 20.8% experienced MACE. Compared with the lowest SBPSD quartile (quartile 1), the risk of all-cause mortality was 35% higher for the highest quartile (quartile 4), while controlling for covariates (HR = 1.35; 95% CI, 1.13-1.61). The risk of CVD mortality and MACE was higher for quartile 4 SBPSD compared with quartile 1 (CVD mortality, HR = 1.81, 95% CI, 1.29-2.53; MACE HR = 1.39, 95 % CI, 1.07-1.80). The risk for quartile 4 DBPSD was not significant for these outcomes (all-cause mortality, HR = 1.15, 95% CI, 0.97-1.36; CVD mortality, HR=1.22, 95% CI, 0.91-1.65; MACE, HR = 1.11, 95% CI, 0.87-1.40). CONCLUSION: Our study identified SBPSD as a significant risk factor for all-cause mortality, cardiovascular mortality, and MACE, whereas DBPSD in our cohort of American Indian subjects was not a significant risk factor after adjustment for covariates.