OBJECTIVES: Fidaxomicin is the first in a new class of macrocylic antibiotics, indicated for the treatment of adults with Clostridium difficile infection (CDI) also known as C. difficile-associated diarrhoea (CDAD). Two phase III comparative clinical studies showed that fidaxomicin was non-inferior to vancomycin for clinical cure, and superior for recurrence and sustained clinical cure. The study objective was to perform a cost-effectiveness analysis of fidaxomicin for the treatment of severe CDI and the first severe recurrence compared to oral vancomycin from a Swedish healthcare perspective. METHODS: A Markov model was developed to analyse the cost-effectiveness of fidaxomicin compared to vancomycin in the treatment of patients with severe CDI, and patients with initial severe CDI recurrences, respectively. The patient enters the model in the CDI health state and is treated either with fidaxomicin or vancomycin. Each treatment cycle was 10 days and the total time horizon was one-year. Deterministic and probabilistic sensitivity analyses were performed. Health state utilities were derived from the literature. RESULTS: Fidaxomicin was associated with an increased cost per patient in the severe CDI population and was cost-saving in severe recurrent CDI patients. A utility gain was demonstrated in both fidaxomicin patient populations. The ICER was SEK 83,159 per QALY for severe CDI and dominant for patients with a severe CDI recurrence (ICER = SEK -92,738 per QALY). Sensitivity analyses found the results to be robust. (1 EURO = 9.07 SEK). CONCLUSIONS: Fidaxomicin was cost-effective in severe CDI and dominant in patients with a severe CDI recurrence from a Swedish healthcare perspective.