PURPOSE: The goals of this study were to assess prospectively the impact of obesity, alcohol use, and smoking on total mortality and to test the etiologic hypothesis that subjects with two or more of these risk factors may experience an elevated risk of overall mortality. METHODS: Information on body mass index (BMI), alcohol intake, cigarette smoking, and other life-style factors was obtained from a cohort of 8006 Japanese-American men living in Hawaii. They were between 45 and 68 years of age at the initial examination (1965-1968). After 22 years of follow-up that included nearly 159,000 person-years of observation, 2667 deaths from all causes were identified. RESULTS: There was a significant quadratic (J-shaped) relation between BMI and overall mortality. A weaker J-shaped pattern in risk was also present for the intake of alcohol. A strong positive association was observed with pack-years of cigarette smoking. A synergistic interaction between BMI and alcohol was statistically significant (P = 0.0017). Specifically, men who had the lowest body mass (BMI < 21.21 kg/m2) and drank moderately to heavily (> or = 25 oz/mo) experienced a 63% excess risk (relative risk, 1.63; 95% confidence interval; 1.33 - 1.99) compared to a reference group composed of men who had intermediate body mass (BMI, 21.21 - 26.30 kg/m2) and drank occasionally to lightly (0.01 - 24.99 oz/mo). The increase in risk due to the interactive effect of low BMI and high alcohol intake was stronger (and statistically significant) than when each of these risk factors was considered separately (excess risk, 28% and 2%, respectively). There was no significant interaction for BMI and cigarette smoking, for alcohol and cigarette smoking, or for the three factors combined. CONCLUSIONS: The most important finding of this study was that, in addition to confirming that cigarette smoking could shorten life, extreme (high or low) BMI values and high alcohol consumption are each potentially harmful to health, but even more so if moderate or heavy drinking is concomitant with low body mass, a possible indicator for low intake of nutrients.