OBJECTIVES: There is mixed evidence regarding the risk of C. difficile infection due to use of Proton Pump Inhibitors (PPIs). This study examined the risk of C. difficile infection associated with the use of PPIs among community dwelling adults with Gastroesophageal Reflux Disease (GERD). METHODS: The study involved a nested case-control design using Truven Health Analytics 2003-2004 MarketScan database. Participants included adults aged more than 18 years, diagnosed with GERD anytime between January 1, 2003, and December 31, 2004 and no history of C. difficile infection between January 1, 2003 and June 30, 2003. Cases were identified as enrollees with an incident diagnosis of C. difficile infection, between July 1, 2003, and December 31, 2004 (n=97). Four age- and gender-matched controls (n=388) were identified per case using incident density sampling. A conditional logistic regression model stratified on matched case-control sets was used to evaluate the risk of C. difficile infection. RESULTS: The study sample consisted of 97 cases diagnosed with C. difficile infection and 388 age- and sex-matched controls. Cases had a higher Elixhauser Comorbidity Index (1.99 versus 0.34, p-value <.0001) compared to controls. The conditional logistic model revealed that the use of PPIs was not significantly associated with risk of C. difficile infection (Odds ratio (OR): 1.24, 95% Confidence Interval (CI): 0.57-2.68). Previous hospitalization (OR: 46, 95% CI: 9.26-228.59), previous antibiotic exposure (low-risk (OR: 1.07, 95% CI: 1.02-1.12), medium-risk (OR: 1.22, 95% CI: 1.09-1.37) and high-risk (OR: 1.27, 95% CI: 1.11-1.46)), abdominal pain (OR: 4.10, 95% CI: 1.73-9.69) and disease severity (OR: 1.22, 95% CI: 1.02-1.46) showed increased risk of C. difficile infection CONCLUSIONS: Overall, PPIs were not associated with risk of C. difficile infection among community dwelling adults with an indication for GERD. More research is needed in other healthcare settings to understand PPIs safety profile, especially for long term use.