Insulin-like growth factor (IGF)-I has growth-promoting effects on pancreatic cancer cells, and elevated fasting serum insulin has been linked to pancreatic cancer risk. IGF binding protein-1 (IGFBP-1) is a downstream target of insulin and inhibits IGF-I activity. To investigate whether prediagnostic plasma levels of IGFBP-1 are associated with pancreatic cancer risk, we did a prospective, case-control study nested within the Health Professionals Follow-up Study, the Nurses' Health Study, the Physicians' Health Study, and the Women's Health Initiative. We assayed circulating IGFBP-1 among 144 pancreatic cancer cases that occurred >or=4 years after plasma collection and in 429 controls, matched for date of birth, prospective cohort, smoking status, and fasting status. When compared with participants in the three highest quartiles of plasma IGFBP-1, those in the lowest quartile experienced a relative risk (RR) for pancreatic cancer of 2.07 [95% confidence intervals (95% CI), 1.26-3.39], after adjusting for other risk factors, including circulating IGF-I, IGF binding protein-3, and C-peptide. Only participants in the lowest quartile of plasma IGFBP-1 showed an elevated risk of pancreatic cancer. The influence of low plasma IGFBP-1 became progressively stronger with time; among cases diagnosed >or=8 years after blood collection, the adjusted RR was 3.47 (95% CI, 1.48-8.14), comparing the bottom versus the top three quartiles. The influence of plasma IGFBP-1 was most marked among participants who never smoked cigarettes (RR, 3.30; 95% CI, 1.48-7.35). Among participants in four U.S. prospective cohort studies, low plasma IGFBP-1 levels significantly predicted an increased risk of pancreatic cancer.