Samples and data are analyzed from a longitudinal population study (1965 to 2007) that allows study of the risk factors and effects of diabetes mellitus. Long-term observations, up to 40 years, confirmed the profound effect of pre-existing diabetes or abnormal glucose tolerance in pregnancy on the risk of diabetes in the offspring. Among nondiabetic children, a number of risk factors, including parental diabetes, body size measurements and glucose and insulin concentrations, predict development of diabetes by young adulthood. Individual estimates of risk can be made to assist in identifying children and adolescents at highest risk of developing diabetes so that more intensive intervention can be offered. Largely due to increasing obesity in children and the vicious cycle of increasing prevalence of diabetes in pregnancy, the incidence of type 2 diabetes in Pima Indian children and adolescents has increased dramatically over the last few decades, despite relatively little change in incidence rates in adults. Increasing prevalence of type 2 diabetes in youth leads to long-term complications such as renal failure occurring in middle adulthood and perpetuates the vicious cycle of diabetes in pregnancy begetting diabetes in the offspring. We assessed whether body mass index (BMI), glucose tolerance, blood pressure and cholesterolemia in 4,857 American Indian non-diabetic children (mean age 11.3 years;N=12,659 examinations) born 19451984 predict premature mortality. Proportional hazards models were used to assess whether each age-standardized risk factor was associated with time to death occurring before age 55 years. For children in the highest BMI quartile, death rates from natural causes were more than double those of children in the lowest BMI quartile (hazard rate ratio, HRR: 2.30;95% CI:1.463.62). Natural-cause death rates in children in the highest quartile of glucose intolerance were 73% greater than those in the lowest quartile (HRR: 1.73;95% CI:1.092.74). No statistically significant associations were observed for childhood blood pressure or cholesterolemia. Obesity and glucose intolerance in childhood are strongly associated with increased adult premature mortality in this population. By contrast, childhood blood pressure and hypercholesterolemia did not predictor such mortality. This information suggests that childhood obesity is a major modifiable risk factor for premature death.