OBJECTIVES: Increasing rates of Clostridium Difficile Infection (CDI), a hospital-acquired infection, has stimulated a number of financial incentives and government sponsored initiatives to quell the spread of the disease.  Previous research has shown the impact of CDI on hospital length of stay to attempt to quantify the resource implications.  The purpose of this study is to evaluate the impact of CDI on in-hospital mortality. METHODS: Data were obtained from national hospital episode databases in England, The Netherlands, and Spain.  Only patients over the age of 50 and those diagnosed with diabetes, chronic kidney disease, heart failure, and chronic obstructive pulmonary disease (COPD) were included in the analysis.  Cases of CDI were stratified between hospital-onset and community-onset cases.  Only those that were assumed to be hospital-onset were included in the analysis.  A logistical regression was used to predict the relative effect hospital-onset CDI had on in-hospital mortality.  A number of covariates were controlled for including: age, sex, comorbidities, and length of stay but varied between countries depending on the availability of data. RESULTS: Patients with hospital-onset CDI had an overall higher mortality rate compared to those who did not have the disease, demonstrated by a crude relative risk of 6.06 in England (37.6% vs. 6.2%), 2.68 in The Netherlands (19.0% vs. 7.1%), and 1.97 in Spain (14.9% vs. 7.5%).  When controlling for covariates, predictive models found a considerable impact of hospital-onset CDI on mortality with odds ratios of 2.57 for England (p<0.001), 1.88 for The Netherlands (p<0.001) and 1.33 for Spain (p<0.001). CONCLUSIONS: This research demonstrates the significant impact of CDI on hospital mortality and the need for more preventative measures within the hospital setting.  Further research using death certificate data could improve the predictive results of models by ensuring that causal effects of CDI are accurately accounted for.