The incidence of Clostridium difficile infection (CDI) is increasing among hospitalized patients. Liver transplantation (LT) patients are at higher risk for acquiring CDI. Small, single-center studies (but no nationwide analyses) have assessed this association. We used the Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project (2004-2008) for this retrospective, cross-sectional study. Patients with any discharge diagnosis of LT composed the study population, and they were identified with International Classification of Diseases, Ninth Revision, Clinical Modification codes. Those with a discharge diagnosis of CDI were considered cases. Our primary outcomes were the prevalence of CDI and the effects of CDI on inpatient mortality. Our secondary outcomes included the length of stay and hospitalization charges. A regression analysis was used to derive odds ratios (ORs) adjusted for potential confounders. There were 193,174 discharges with a diagnosis of LT from 2004 to 2008. The prevalence of CDI was 2.7% in the LT population and 0.9% in the non-LT population (P < 0.001). Most of the LT patients were 50 to 64 years old. LT patients had higher odds of developing CDI [OR = 2.88, 95% confidence interval (CI) = 2.68-3.10]. Increasing age and increasing comorbidity (including inflammatory bowel disease and nasogastric tube placement) were also independent CDI risk factors. CDI was associated with a higher mortality rate: 5.5% for LT patients with CDI versus 3.2% for LT-only patients (adjusted OR = 1.70, 95% CI = 1.29-2.25). In conclusion, the prevalence of CDI is higher for LT patients versus non-LT patients (2.7% versus 0.9%). CDI is an independent risk factor for mortality in the LT population. Liver Transpl, 2012. © 2012 AASLD.