BACKGROUND: Pancreatic cancer is among the most fatal human cancers and the fourth leading cause of cancer death in the United States. Evidence suggests that chronic inflammation may play a role in pancreatic carcinogenesis and its inhibition through nonsteroidal anti-inflammatory drugs (NSAID) may reduce pancreatic cancer incidence. METHODS: We examined associations of total and individual NSAIDs with pancreatic cancer risk among postmenopausal women participating in the Women's Health Initiative observational study and clinical trial cohorts. Among 117,452 women, aged 55 to 79 years, 727 incident pancreatic cancer cases were reported over 18 years of follow-up. Cox regression was used to estimate hazard ratio (HR) and 95% confidence interval (CI) for associations between NSAIDs and pancreatic cancer risk. RESULTS: Relative to non-use, consistent use of any NSAID was inversely associated with pancreatic cancer risk (HR 0.71, 95% CI, 0.59-0.87), primarily driven by strong associations for aspirin use (HR 0.67, 95% CI, 0.52-0.86). Use of total or individual non-aspirin NSAIDs was not associated with pancreatic cancer. Upon stratified analysis, we observed stronger associations for NSAIDs among participants with prevalent diabetes (HR 0.28, 95% CI, 0.10-0.75) relative to those without (HR 0.75, 95% CI, 0.61-0.92; P-interaction = 0.03). CONCLUSIONS: Additional large prospective studies with careful measurement of NSAID type, dose, and frequency are needed to further investigate the possibility of added benefit among individuals diagnosed with diabetes. IMPACT: This study adds to existing evidence from prospective studies and clinical trials suggesting that use of aspirin may provide moderate benefit for pancreatic cancer prevention.