OBJECTIVES: Clostridium difficile infection (CDI) is one of the most common hospital acquired infections in industrialised countries. CDI is responsible for severe morbidity, partly driven by the high proportion of patients experiencing a recurrence after an initial successful response to treatment. In Belgium, CDI incidence and mortality has more than doubled between 1998 and 2007. The aim of this study was to assess the cost-utility of fidaxomicin as compared to current standard treatment for managing CDI in Belgium.  METHODS: A Markov model with a 1-year time horizon and 10-day cycles was developed to compare fidaxomicin, metronidazole and vancomycin in patients with all CDI and two subpopulations (severe CDI and first recurrence of CDI). Clinical data from two pooled published phase-3 trials (fidaxomicin vs. vancomycin) were used along a mixed treatment comparison of fidaxomicin vs. metronidazole. Treatment paths and data input were approved during an advisory board. Costs of first episode and recurrent CDI hospitalizations were taken from the IMS Hospital Disease Database. Cost per quality-adjusted life-year (QALY) gained was calculated from the health care payer perspective.  RESULTS: The model showed cost savings and QALY gained versus vancomycin and metronidazole. Fidaxomicin versus an average of these comparators delivered benefits for all CDI patients (-1,100€; 0.008 QALY), for severe CDI (-1,300€; 0.009 QALY) and for first recurrence CDI (-1,500€; 0.009 QALY). One-way sensitivity analyses revealed that time horizon and the odds ratio of recurrence with fidaxomicin had most affect on the results.  Applying a cost-effectiveness threshold of €30,000 per QALY gained, probabilistic sensitivity analysis showed acceptable cost-effectiveness in 80% of all CDI cases.  CONCLUSIONS: Based on the available clinical data the model showed that fidaxomicin dominates vancomycin and metronidazole generating additional QALYs with cost-savings not only in patients with all CDI, but also in subpopulations with severe CDI or a first recurrence.