In a 12-year prospective study, the authors examined the relation between body mass index (BMI) and mortality among the 20,346 middle-aged (25-54 years) and older (55-84 years) non-Hispanic white cohort members of the Adventist Health Study (California, 1976-1988) who had never smoked cigarettes and had no history of coronary heart disease, cancer, or stroke. In analyses that accounted for putative indicators (weight change relative to 17 years before baseline, death during early follow-up) of pre-existing illness, the authors found a direct positive relation between BMI and all-cause mortality among middle-aged men (minimum risk at BMI (kg/m2) 15-22.3, older men (minimum risk at BMI 13.5-22.3), middle-aged women (minimum risk at BMI 13.9-20.6), and older women who had undergone postmenopausal hormone replacement (minimum risk at BMI 13.4-20.6). Among older women who had not undergone postmenopausal hormone replacement, the authors found a J-shaped relation (minimum risk at BMI 20.7-27.4) in which BMI <20.7 was associated with a twofold increase in mortality risk (hazard ratio (HR) = 2.2, 95% confidence interval (CI) 1.3, 3.5) that was primarily due to cardiovascular and respiratory disease. These findings not only identify adiposity as a risk factor among adults, but also raise the possibility that very lean older women can experience an increased mortality risk that may be due to their lower levels of adipose tissue-derived estrogen.