Purpose: Preclinical studies have suggested that proton pump inhibitors (PPIs) mayincrease pancreatic cancer risk; however, epidemiological studies are few, with con-flicting results. This spurred us to evaluate whether PPI use is associated with anincreased risk of pancreatic cancer in a large population‐based study.Methods: We conducted a nationwide case‐control study using data from Danishdemographic and health care registries. All patients with a first cancer diagnosis of pancre-atic cancer between 2000 and 2015 were identified from the Danish Cancer Registry andage‐matched, sex‐matched, and calendar‐matched 1:20 to population controls using riskset sampling. Conditional logistic regression was applied to calculate odds ratios (ORs) and95% confidence intervals (CIs) for pancreatic cancer associated with PPI use, adjusting forpotential confounders. Secondary analyses examined dose‐response patterns and associ-ations with individual PPIs as well as with histamine‐2‐receptor antagonists.Results: Ever use of PPIs occurred among 27.8% of 6921 pancreatic cancer casesand 25.4% of 34 695 matched controls, yielding a neutral adjusted OR of 1.04 (95%CI 0.97‐1.11). Odds ratios were also close to unity in analyses of high use of PPIs(≥1000 DDDs; OR, 0.92 95% CI 0.80‐1.07). There was no evidence of a dose‐response relationship, with ORs close to unity across categories, including for thosewith the highest cumulative use (>2000 DDDs; OR, 1.03 95% CI 0.84‐1.26). Analysesof subgroups as well as individual types of PPI and of histamine‐2‐ receptor antago-nists use also returned neutral associations.Conclusions: In this large nationwide case‐control study, PPI use was not associ-ated with an increased risk of pancreatic cancer.