Between 2001 and 2005, Blacks from the United States experienced a 32% higher pancreatic cancer death rate than Whites. Smoking, diabetes, and family history might explain some of this disparity, but prospective analyses are warranted. From 1984 to 2004, there were 6,243 pancreatic cancer deaths among Blacks (n = 48,525) and Whites (n = 1,011,864) in the Cancer Prevention Study II cohort. Multivariate Cox proportional hazards models yielded hazards ratios (HR) for known and suspected risk factors. Population attributable risks were computed and their effect on age-standardized mortality rates were evaluated. Blacks in this cohort had a 42% increased risk of pancreatic cancer mortality compared with Whites (HR, 1.42; 95% confidence intervals (CI), 1.28-1.58). Current smoking increased risk by >60% in both races; although Blacks smoked less intensely, risks were similar to Whites (HR(Black), 1.67; 95% CI, 1.28-2.18; HR(White), 1.82; 95% CI, 1.7-1.95). Obesity was significantly associated with pancreatic cancer mortality in Black men (HR, 1.66; 95% CI, 1.05-2.63), White men (HR, 1.42; 95% CI, 1.25-1.60), and White women (HR, 1.37; 95% CI, 1.22-1.54); results were null in Black women. The population attributable risk due to smoking, family history, diabetes, cholecystectomy, and overweight/obesity was 24.3% in Whites and 21.8% in Blacks. Smoking and overweight/obesity play a substantial a role in pancreatic cancer. Variation in the effect of these factors underscores the need to evaluate disease on the race-sex level. The inability to attribute excess disease in Blacks to currently known risk factors, even when combined with suspected risks, points to yet undetermined factors that play a role in the disease process.