Remaining controversies on the association between body mass index (BMI) and mortality include the effects of smoking and prevalent disease on the association, whether overweight is associated with higher mortality rates, differences in associations by race and the optimal age at which BMI predicts mortality. To assess the relative risk (RR) of mortality by BMI in Whites and Blacks among subgroups defined by smoking, prevalent disease, and age, 891,572 White and 38,119 Black men and women provided height, weight and other information when enrolled in the Cancer Prevention Study II in 1982. Over 28 years of follow-up, there were 434,400 deaths in Whites and 18,702 deaths in Blacks. Cox proportional-hazards regression was used to estimate multivariable-adjusted relative risks (RR) and 95% confidence intervals (CI). Smoking and prevalent disease status significantly modified the BMI-mortality relationship in Whites and Blacks; higher BMI was most strongly associated with higher risk of mortality among never smokers without prevalent disease. All levels of overweight and obesity were associated with a statistically significantly higher risk of mortality compared to the reference category (BMI 22.5-24.9 kg/m2), except among Black women where risk was elevated but not statistically significant in the lower end of overweight. Although absolute mortality rates were higher in Blacks than Whites within each BMI category, relative risks (RRs) were similar between race groups for both men and women (p-heterogeneity by race = 0.20 for men and 0.23 for women). BMI was most strongly associated with mortality when reported before age 70 years. Results from this study demonstrate for the first time that the BMI-mortality relationship differs for men and women who smoke or have prevalent disease compared to healthy never-smokers. These findings further support recommendations for maintaining a BMI between 20-25 kg/m2 for optimal health and longevity.