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Abstract Background Heart disease and stroke are among the leading causes of death in Native Americans. Knowledge of heart attack and stroke symptomology are essential for prompt identification of symptoms and for appropriate action in seeking care. Knowledge of heart attack and stroke symptoms among US Native American adults was this study’s focus. Methods Multivariate techniques were used to analyze national surveillance data. Native American adults comprised the study population. Low heart attack and stroke knowledge score was the dependent variable. Results Logistic regression analysis yielded that Native American adults with low heart attack and stroke composite knowledge scores were more likely to be: older, less educated, poorer, uninsured, a rural resident, male, without a primary health care provider, and lacking a recent medical checkup. Conclusions The identified characteristics of Native American adults with heart attack and stroke knowledge deficits or disparities should guide educational initiatives by health care providers focusing on improving such knowledge.