The authors examined the association between waist circumference and mortality among 154,776 men and 90,757 women aged 51–72 years at baseline (1996–1997) in the NIH-AARP Diet and Health Study. Additionally, the combined effects of waist circumference and body mass index (BMI; weight (kg)/height (m)²) were examined. All-cause mortality was assessed over 9 years of follow-up (1996–2005). After adjustment for BMI and other covariates, a large waist circumference (fifth quintile vs. second) was associated with an approximately 25% increased mortality risk (men: hazard ratio (HR) = 1.22, 95% confidence interval (CI): 1.15, 1.29; women: HR = 1.28, 95% CI: 1.16, 1.41). The waist circumference-mortality association was found in persons with and without prevalent disease, in smokers and nonsmokers, and across different racial/ethnic groups (non-Hispanic Whites, non-Hispanic Blacks, Hispanics, and Asians). Compared with subjects with a combination of normal BMI (18.5–<25) and normal waist circumference, those in the normal-BMI group with a large waist circumference (men: ≥102 cm; women: ≥88 cm) had an approximately 20% higher mortality risk (men: HR = 1.23, 95% CI: 1.08, 1.39; women: HR = 1.22, 95% CI: 1.09, 1.36). The finding that persons with a normal BMI but a large waist circumference had a higher mortality risk in this study suggests that increased waist circumference should be considered a risk factor for mortality, in addition to BMI.