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Proton pump inhibitors (PPIs) have been associated with increased risk of infection, likely because of changes in intestinal epithelial permeability and the gastrointestinal microbiome. PPIs are frequently given to patients in the intensive care unit (ICU) to prevent stress ulcers. These patients are at risk for bloodstream infections (BSIs), so we investigated the relationship between PPI use and BSIs among patients in the ICU.We performed a retrospective cohort study of adults (≥18 years) admitted to 1 of 14 ICUs within a hospital network of 3 large hospitals from 2008 through 2014. The primary exposure was PPI use for stress ulcer prophylaxis in the ICU. The primary outcome was BSI, confirmed by culture analysis, arising 48 hours or more after admission to the ICU. Subjects were followed for 30 days after ICU admission or until death, discharge, or BSI. Multivariable Cox proportional hazards modeling was used to test the association between PPIs and BSI after controlling for patient comorbidities and other clinical factors.We analyzed data from 24,774 patients in the ICU, including 756 patients (3.1%) who developed BSIs while in the ICU. The cumulative incidence of BSI was 3.7% in patients with PPI exposure compared with 2.2% in patients without PPI exposure (log-rank test,P< .01). After adjusting for potential confounders, PPI exposure was not associated with increased risk of BSI while in the ICU (adjusted hazard ratio, 1.08; 95% confidence interval, 0.91–1.29). Comorbidities, antibiotic use, and mechanical ventilation were all independently associated with increased risk for BSIs.In a retrospective study of patients in the ICU, administration of PPIs to prevent bleeding was not associated with increased risk of BSI. These findings indicate that concern for BSI should not affect decisions regarding use of PPIs in the ICU.