Lifestyle factors such as smoking, alcohol, body weight, physical activity, and diet quality have been associated with the risk of pancreatic cancer. However, studies of their combined association in women are limited. Data on smoking habits, alcohol intake, diet composition, recreational physical activity, body weight, and waist circumference, obtained at recruitment for 136,945 postmenopausal women (aged 50-79years) participating in the Women's Health Initiative study, were categorized separately, with higher scores for each variable assigned to the categories representing healthier behaviors. The combined healthy lifestyle index (HLI) score, created by summing the scores for each risk factor, was grouped into quartiles. We used multivariable-adjusted Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for pancreatic cancer risk in association with the HLI. Over an average follow-up period of approximately 16.0years, 1,119 incident cases of pancreatic cancer were ascertained. Compared to women in the lowest HLI quartile, those in the upper quartiles (qt) had a reduced risk of pancreatic cancer (multivariable-adjusted HRqt3rd 0.83, 95% CI 0.74-0.99; and HRqt4th 0.74, 95% CI 0.62-0.88, respectively, p trend = 0.001). Use of waist circumference instead of BMI in the HLI score yielded similar results. Among women who were either non-diabetic or non-smokers, high HLI was also associated with reduced risk (HRqt4th 0.78, 95% CI 0.65-0.85 and HRqt4th 0.80, 95% CI 0.66-0.97, respectively). Stratification by BMI categories (18.5- < 25.0, 25.0- < 30.0 and > 30.0kg/m2) showed similar results in all groups. Our findings suggest that in postmenopausal women, a healthy lifestyle is associated with reduced risk of pancreatic cancer.