The relationship between body mass index (BMI) and mortality is controversial. To investigate the relationship between maximum BMI over 16 years and subsequent mortality. 3 prospective cohort studies. Nurses' Health Study I and II and Health Professionals Follow-Up Study. 225072 men and women with 32571 deaths observed over a mean of 12.3 years of follow-up. Maximum BMI over 16 years of weight history and all-cause and cause-specific mortality. Maximum BMIs in the overweight (25.0 to 29.9 kg/m2) (multivariate hazard ratio [HR], 1.06 [95% CI, 1.03 to 1.08]), obese I (30.0 to 34.9 kg/m2) (HR, 1.24 [CI, 1.20 to 1.29]), and obese II (≥35.0 kg/m2) (HR, 1.73 [CI, 1.66 to 1.80]) categories were associated with increases in risk for all-cause death. The pattern of excess risk with a maximum BMI above normal weight was maintained across strata defined by smoking status, sex, and age, but the excess was greatest among those younger than 70 years and never-smokers. In contrast, a significant inverse association between overweight and mortality (HR, 0.96 [CI, 0.94 to 0.99]) was observed when BMI was defined using a single baseline measurement. Maximum overweight was also associated with increased cause-specific mortality, including death from cardiovascular disease and coronary heart disease. Residual confounding and misclassification. The paradoxical association between overweight and mortality is reversed in analyses incorporating weight history. Maximum BMI may be a useful metric to minimize reverse causation bias associated with a single baseline BMI assessment. National Institutes of Health.