Background: Several epidemiologic studies have examined the association between physical activity and pancreatic cancer risk; however, the results of these studies are not consistent. Methods: This study examined the associations of total, moderate, and vigorous physical activity to pancreatic cancer in a cohort of 33,530 U. S. women enrolled in the Breast Cancer Detection Demonstration Project ( BCDDP). At baseline ( 1987 - 1989), information on physical activity over the past year was obtained using a self-administered questionnaire. Cox proportional hazards regression was used to estimate relative risks ( RR) and 95% confidence intervals of pancreatic cancer risk. Results: 70 incident cases of pancreatic cancer were ascertained during 284,639 person years of follow-up between 1987 - 1989 and 1995 - 1998. After adjustment for age, body mass index, smoking status, history of diabetes, and height, increased physical activity was related to a suggestively decreased risk of pancreatic cancer. The RRs for increasing quartiles of total physical activity were 1.0, 0.80, 0.66, 0.52 ( 95% CI = 0.26, 1.05; P-trend = 0.05). This association was consistent across subgroups defined by body mass index and smoking status. We also observed statistically nonsignificant reductions in pancreatic cancer risk for women in the highest quartile of moderate ( RR = 0.57; 95% CI = 0.26, 1.26) and highest quartile of vigorous physical activity ( RR = 0.63; 95% CI = 0.31, 1.28) compared to their least active counterparts. Conclusion: Our study provides evidence for a role of physical activity in protecting against pancreatic cancer.