There is increasing evidence that type 2 diabetes mellitus and glucose intolerance are a cause, not just a consequence, of pancreatic cancer. We examined whether other factors that characterize the insulin resistance syndrome are also risk factors for pancreatic cancer in a prospective cohort study of 631,172 men and women (ages 45+ years) who received health insurance from the Korean Medical Insurance Corporation. The biennial medical evaluations from 1992 to 1995 provided the baseline information for this study. Relative risks (RR) were estimated using proportional hazards models adjusted for age, sex, smoking, and fasting serum glucose (after excluding the first 2 years of follow-up). There were 2,194 incident cases of pancreatic cancer diagnosed in the cohort over a median follow-up of 12 years. There was no evidence that pancreatic cancer risk was associated with total cholesterol, systolic blood pressure, WBC count, or body mass index. Abnormal levels of aspartate aminotransferase and alanine aminotransferase were both associated with a moderately increased risk of developing the disease (40+ versus <20; RR, 1.33; 95% CI, 1.14-1.55; P(trend) = 0.05 and RR, 1.34; 95% CI, 1.16-1.56; P(trend) = 0.02, respectively). Excluding 6 years of follow-up reduced this RR (95% CI) for aspartate aminotransferase to 1.22 (1.01-1.49), but even after excluding 10 years follow-up the RR (95% CI) for alanine aminotransferase was unchanged [1.36 (1.01-1.83)]. Although fasting serum glucose has been found previously to be associated with pancreatic cancer risk in this cohort, most other factors that characterize insulin resistance syndrome were not associated with pancreatic cancer risk. The association with elevated liver enzyme levels is a novel finding that warrants further investigation.