Clostridium difficile infection (CDI) is the most common cause of nosocomial diarrhea. Patients with end-stage renal disease (ESRD) may be at increased risk for CDI. Patients with ESRD with CDI have increased mortality, longer length of stay, and higher costs. The present studies extend these observations and address associated comorbidities, incidence of recurrence, and risk factors for mortality. We queried the United States Renal Data System (USRDS) for patients with ESRD diagnosed with CDI, and assessed for the incidence of infection, comorbidities, and mortality. The records of 419,875 incident dialysis patients from 2005 to 2008 were reviewed. 4.25% had a diagnosis of a first CDI. In the majority of patients with CDI positive, a hospitalization or ICU stay was documented within 90 days prior to the diagnosis of CDI. The greatest adjusted relative risk (aRR) of CDI was present in patients with HIV (aRR 2.68), age ≥65 years (aRR 1.76), and bacteremia (aRR 1.74). The adjusted HR (aHR) for death was 1.80 in patients with CDI. The comorbidities demonstrating the greatest risk for death in dialysis patients with CDI included age ≥65 years and cirrhosis (aHR 2.28 and 1.76, respectively). Recurrent CDI occurred in 23.6%, was more common in Caucasians, and in those who were older. CDI is a common occurrence in patients with ESRD, with elderly patients, patients with HIV positive, and bacteremic patients at highest risk for infection. Patients with CDI had nearly a twofold increased risk of death.