BACKGROUND: Smoking and high adiposity are strong independent health risk factors but are also interrelated. Smoking is related to a lower body mass index (BMI) but not necessarily with a smaller waist circumference. Smoking cessation is associated with increased body weight and a substantial increase in waist circumference. How this affects mortality risk is unknown. OBJECTIVE: This study examined the combined relations of smoking status with BMI and waist circumference and smoking status to all-cause mortality. DESIGN: Data were from 149 502 men and 88 184 women aged 51-72 y participating in the National Institutes of Health-AARP Diet and Health Study. All-cause mortality was assessed over 10 y of follow-up from 1996 to 2006. RESULTS: Current smokers with a BMI (in kg/m(2)) <18.5 or >or=35 had a mortality risk 6-8 times that of persons within the normal BMI range who never smoked. Current smokers with a large waist circumference had a mortality risk about 5 times that of never smokers with a waist circumference in the second quintile. CONCLUSION: Both smoking and adiposity are independent predictors of mortality, but the combination of current or recent smoking with a BMI >or= 35 or a large waist circumference is related to an especially high mortality risk.