Increased incidence and severity of Clostridium difficile infections (CDIs) is of major concern. However, by minimizing known risk factors, the incidence can be decreased. The aim of this investigation was to calculate the incidence and assess risk factors for CDI in our population. A 1-year prospective population-based nationwide study in Iceland of CDIs was carried out. For risk factor evaluation, each case was matched with two age- and sex-matched controls that tested negative for C. difficile toxin. A total of 128 CDIs were identified. The crude incidence was 54 cases annually per 100,000 population >18 years of age. Incidence increased exponentially with older age (319 per 100,000 population >86 years of age). Community-acquired origin was 27?%. Independent risk factors included: dicloxacillin (odds ratio [OR]: 7.55, 95?% confidence interval [CI]: 1.89-30.1), clindamycin (OR: 6.09, 95?% CI: 2.23-16.61), ceftriaxone (OR: 4.28, 95?% CI: 1.59-11.49), living in a retirement home (OR: 3.9, 95?% CI: 1.69-9.16), recent hospital stay (OR: 2.3, 95?% CI: 1.37-3.87). Proton pump inhibitors (PPIs) were used by 60/111 (54?%) versus 91/222 (41?%) (p?=?0.026) and ciprofloxacin 19/111 (17?%) versus 19/222 (9?%) (p?=?0.027) for cases and controls, respectively. In all, 75?% of primary CDIs treated with metronidazole recovered from one course of treatment. CDI was mostly found among elderly patients. The most commonly identified risk factors were broad-spectrum antibiotics and recent contact with health care institutions. PPI use was significantly more prevalent among CDI patients.