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To examine the incidence ofCampylobacterandSalmonellainfection in patients prescribed proton pump inhibitors (PPIs) compared with controls.Retrospective cohort study using anonymous general practitioner (GP) data. Anonymised individual-level records from the Secure Anonymised Information Linkage (SAIL) system between 1990 and 2010 in Wales were selected. Data were available from 1,913,925 individuals including 358,938 prescribed a PPI. The main outcome measures examined included incidence ofCampylobacterorSalmonellainfection following a prescription for PPI.The rate ofCampylobacterandSalmonellainfections was already at 3.1–6.9 times that of non-PPI patients even before PPI prescription. The PPI group had an increased hazard rate of infection (after prescription for PPI) of 1.46 forCampylobacterand 1.2 forSalmonella, compared with baseline. However, the non-PPI patients also had an increased hazard ratio with time. In fact, the ratio of events in the PPI group compared with the non-PPI group using the prior event rate ratio was 1.17 (95% CI 0.74–1.61) forCampylobacterand 1.00 (0.5–1.5) forSalmonella.People who go on to be prescribed PPIs have a greater underlying risk of gastrointestinal (GI) infection beforehand and they have a higher prevalence of risk factors before PPI prescription. The rate of diagnosis of infection is increasing with time regardless of PPI use, and there is no evidence that PPI is associated with an increase in diagnosed GI infection. It is likely that factors associated with the demographic profile of the patient are the main contributors to increased rate of GI infection for patients prescribed PPIs.