OBJECTIVES To estimate the incidence and identified risk factors for community-acquired (CA) and hospital-acquired (HA) Clostridium difficile infection (CDI) METHODS We conducted 2 parallel case-control studies at Tel Aviv Sourasky Medical Center from January 1, 2011, to December 31, 2014. We identified persons with CDI, determined whether infection was community or hospital acquired, and calculated incidence rates from 2007 to 2014. We collected demographic, clinical, and epidemiological information for CDI cases and hospitalized control cases and estimated the odds ratio with 95% confidence interval using conditional logistic regression. RESULTS In total, 1,563 CDI cases were identified in the study. The incidence rate of CA-CDI and HA-CDI increased by 1.6-fold and 1.2-fold, respectively, during 2012-2014. However, the incidence rate of CA-CDI was 0.84 per 100,000 (95% CI, 0.52-1.30), the rate for HA-CDI was 4.7 per 10,000 patient days (95% CI, 4.08-5.38), respectively, in 2014. We identified several factors as independent variables significantly associated with HA-CDI: functional disability, presence of nasogastric tube, antibiotic use, chemotherapy, infection by extended-spectrum β-lactamases, and mean of albumin values. Risk factors independently associated with CA-CDI were close contact with a family member who had been hospitalized in the previous 6 months, inflammatory bowel disease, and home density index (adjusted odds ratio, 25.7; 95% confidence interval, 3.99-165.54; P=.001). CONCLUSIONS The identification of the main modifiable risk factors for HA-CDI (antibiotic exposure and hypoalbuminemia) and for CA-CDI (close contact with a family member who had been hospitalized in the previous 6 months) is likely to optimize prevention efforts; these factors are critical in preventing the spread of CDI. Infect Control Hosp Epidemiol 2017;38:912-920.