In the period April-September 2005, an outbreak of Clostridium difficile infection (CDI) due to PCR ribotype 027 occurred among 50 patients in a 341-bed community hospital in Harderwijk, The Netherlands. A retrospective case-control study was performed to identify risk factors specific for CDI, using a group of patients with CDI (n = 45), a group of randomly selected control patients without diarrhoea (n = 90), and a group of patients with non-infectious diarrhoea (n = 109). Risk factors for CDI and for non-CDI diarrhoea were identified using multiple logistic regression analysis. Independent risk factors for CDI were: age above 65 years (OR 2.6; 95% CI 1.0-5.7), duration of hospitalization (OR 1.04 per additional day; 95% CI 1.0-1.1), and antibiotic use (OR 12.5; 95% CI 3.2-48.1). Of the antibiotics used, cephalosporins and fluoroquinolones were identified as the major risk factors for development of CDI. The risk of developing CDI was particularly high in people receiving a combination of a cephalosporin and a fluoroquinolone (OR 57.5; 95% CI 6.8-483.6). The main factors affecting the risk of non-CDI diarrhoea were proton-pump inhibitors, immunosuppressive drugs, underlying digestive system disease, previous surgery, and gastric tube feeding. The outbreak ended only after implementation of restricted use of cephalosporins and a complete ban on fluoroquinolones, in addition to general hygienic measures, cohorting of patients in a separate ward, education of staff, and intensified environmental cleaning. The results of this study support the importance of appropriate antimicrobial stewardship in the control of hospital outbreaks with C. difficile PCR ribotype 027.