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Objective: To estimate the prevalence and explore the social and cultural etiologic roots of weight status, blood pressure, and acanthosis nigricans among American Indian children on a reservation in South Dakota. Methods: This observational study was conducted in 26 schools from 1998 to 2002 and included 5,422 observations representing 3,841 children, ages 3 to 19. Trained staff measured height, weight, blood pressure, and assessed the presence of acanthosis nigricans (AN). Percent Indian heritage (PIH) was abstracted from tribal records. Sociodemographic environment (SDE) was calculated using the 2000 Census at the city/town level. Descriptive analyses were conducted using one measurement time point, including tests for trend and co-occurrence of risk factors using the [kappa] statistic. Hierarchical, multivariate logistic regression estimated associations with overweight/obesity status, accounting for multiple measures on individuals and SDE. Results: The overall prevalence of overweight/obesity was 46%, of hypertension 9%, and of AN 14%. The co-occurrence of risk factors was moderate to high. PIH and AN were positively associated in unadjusted analysis. Controlling for sex, age, and SDE, higher PIH was a significant correlate of overweight/obesity, although when hypertension (OR = 5.92, CI = 3.27–10.72), prehypertension (OR = 3.80, CI = 1.99–7.26), and AN (OR = 16.20, CI = 8.08–32.48) were included in the model PIH was no longer significant. SDE was not significantly associated with overweight/obesity. Conclusion: PIH appeared to be an important correlate of overweight and obesity, except when adjusted for the co-occurrence of high blood pressure and AN. Overall, the prevalence and co-occurrence of various risk factors in this population was high. Obesity prevention initiatives targeting families and communities are needed, as well as access to screening and treatment services. Am. J. Hum. Biol. 2011. © 2011 Wiley-Liss, Inc.