The epidemiologic evidence for the role of alcohol use in pancreatic cancer development is equivocal. The authors prospectively examined the relation between alcohol use and risk of pancreatic cancer among 470,681 participants who were aged 50-71 years in 1995-1996 in the US National Institutes of Health-AARP Diet and Health Study. The authors identified 1,149 eligible exocrine pancreatic cancer cases through December 2003. Multivariate Cox proportional hazards regression models were used to calculate relative risks and 95% confidence intervals with the referent group being light drinkers (<1 drink/day). The relative risks of developing pancreatic cancer were 1.45 (95% confidence interval (CI): 1.17, 1.80; P(trend) = 0.002) for heavy total alcohol use (>or=3 drinks/day, approximately 40 g of alcohol/day) and 1.62 (95% CI: 1.24, 2.10; P(trend) = 0.001) for heavy liquor use, compared with the respective referent group. The increased risk with heavy total alcohol use was seen in never smokers (relative risk = 1.35, 95% CI: 0.79, 2.30) and participants who quit smoking 10 or more years ago before baseline (relative risk = 1.41, 95% CI: 1.01, 2.00). These findings suggest a moderately increased pancreatic cancer risk with heavy alcohol use, particularly liquor; however, residual confounding by cigarette smoking cannot be completely excluded.