Abstract Background: Pancreatic cancer (PanC) is a rapidly lethal malignancy with poorly understood etiology. Epidemiologic studies show strong associations between PanC and inflammatory conditions or stimuli such as cigarette smoking and diabetes, suggesting that inflammation may play a key role in PanC. Studies of dietary patterns and cancer outcomes also suggest that diet might influence an individual's risk of PanC through modulation of inflammation. We, therefore, examined independent and joint associations between inflammatory potential of diet, cigarette smoking and long-standing type II diabetes (greater than 5 years) in relation to risk of PanC. Methods: Data were from a clinic-based, case-control study of rapidly ascertained patients with incident adenocarcinoma of the exocrine pancreas (n = 819) evaluated at Mayo Clinic and non-cancer control patients (n = 1,769) recruited from Mayo Clinic primary care facilities. Controls were frequency-matched to cases on age, race, and sex. Inflammatory potential of diet was measured using the dietary inflammatory index (DII), calculated from dietary intake assessed via a 144-item food frequency questionnaire and adjusted for energy intake. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for age, sex, race, body mass index, diabetes, smoking, and education. Results: Higher DII scores, reflecting a more pro-inflammatory diet, were associated with increased odds of PanC (OR Quintile5vs1 = 2.80, 95% CI, 2.06–3.79, Ptrend < 0.0001). Increased odds of PanC also were observed among current (OR = 2.55, 95% CI, 1.75–3.72) and former (OR = 1.26, 95% CI, 1.05–1.51) smokers as compared to non- smokers, and among participants with long-standing type II diabetes (OR = 2.96, 95% CI, 1.95–4.51) compared to non-diabetics. Joint associations were observed for the combined effect of having greater than the control median DII score and a) being a current smoker (OR = 4.20, 95% CI, 2.67–6.61),or b) having long-standing type II diabetes (OR = 6.13, 95% CI, 3.47–10.80) as compared to having less than or equal to the control median DII score and being a non-smoker or non-diabetic, respectively. Conclusion: These findings suggest that a pro-inflammatory diet may act synergistically with cigarette smoking and diabetes to increase the risk of PanC beyond the risk of any of these factors alone.