Clostridium difficile is the main infectious cause of colitis in hospital inpatients. The incidence is increasing, and it is associated with significant mortality, morbidity, and increased length of stay. The main risk factor is use of broad-spectrum antibiotics, and antibiotic restriction is the most effective control measure. We carried out a retrospective case-control study to investigate whether use of proton pump inhibitors (PPI) was an additional risk factor. PPI use within the preceding eight weeks was associated with an increased risk of C. difficile diarrhoea (odds ratio 2.5, 95% CI 1.5-4.2). Reduction of unnecessary PPI use may be an additional strategy to reduce the incidence of this infection.