Abstract Background: Only a few studies investigated the association between proton pump inhibitor (PPI) use and pancreatic cancer, with inconsistent results. Moreover, these studies had a number of methodologic limitations. Our objective was to assess this association in a nationwide case–control study. Methods: We used the French National Health Data System (SNDS), covering 99% of the French population since 2006. Incident cases of pancreatic cancer, identified between 2014 and 2018, were matched with up to four controls on year of birth, sex, frequency of hospitalization within 8 years prior to index date, and department of residence. Associations between PPIs and pancreatic cancer were estimated using conditional logistic regression models adjusted for sociodemographic characteristics, risk factors of pancreatic cancer (including diabetes mellitus, tobacco-related diseases, and morbid obesity), and other comorbidities. Results: A total of 23,321 cases of pancreatic cancer (mean age, 69.8 years; 51.7% males) and 75,937 matched controls were included. Overall, 77.8% of cases and 75.5% of controls were PPI ever users. Ever (vs. never) PPI use was associated with an increased risk of pancreatic cancer [adjusted OR (aOR) = 1.05, 95% confidence interval (CI), 1.01–1.09]. A dose–response relationship was observed [1–30 cumulative defined daily dose (cDDD): aOR = 0.92, 95% CI, 0.87–0.97; 31–180 cDDD: aOR = 1.05, 95% CI, 1.00–1.11; 181–1,080 cDDD: aOR = 1.18, 95% CI, 1.12–1.24; >1,080 cDDD: aOR = 1.17, 95% CI, 1.10–1.23]. Conclusions: On the basis of these findings, a slight increase in the risk of pancreatic cancer associated with high cumulative doses of PPIs cannot be excluded. Impact: Given the overuse of PPIs, efforts should be continued to limit treatments to appropriate indications and durations.