Purpose: Preclinical studies have suggested that proton pump inhibitors (PPIs) may increase pancreatic cancer risk; however, epidemiological studies are few, with conflicting results. This spurred us to evaluate whether PPI use is associated with an increased risk of pancreatic cancer in a large population-based study. Methods: We conducted a nationwide case-control study using data from Danish demographic and health care registries. All patients with a first cancer diagnosis of pancreatic cancer between 2000 and 2015 were identified from the Danish Cancer Registry and age-matched, sex-matched, and calendar-matched 1:20 to population controls using risk set sampling. Conditional logistic regression was applied to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for pancreatic cancer associated with PPI use, adjusting for potential confounders. Secondary analyses examined dose-response patterns and associations with individual PPIs as well as with histamine-2-receptor antagonists. Results: Ever use of PPIs occurred among 27.8% of 6921 pancreatic cancer cases and 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 those with the highest cumulative use (>2000 DDDs; OR, 1.03 95% CI 0.84-1.26). Analyses of subgroups as well as individual types of PPI and of histamine-2-receptor antagonists use also returned neutral associations. Conclusions: In this large nationwide case-control study, PPI use was not associated with an increased risk of pancreatic cancer.