The objective of this paper was to assess the cost-utility of fidaxomicin versus vancomycin in the treatment of Clostridium difficile infection (CDI) in three specific CDI patient subgroups: those with cancer, treated with concomitant antibiotic therapy or with renal impairment. A Markov model with six health states was developed to assess the cost-utility of fidaxomicin versus vancomycin in the patient subgroups over a period of 1 year from initial infection. Cost and outcome data used to parameterise the model were taken from Spanish sources and published literature. The costs were from the Spanish hospital perspective, in Euros (€) and for 2013. For CDI patients with cancer, fidaxomicin was dominant versus vancomycin [gain of 0.016 quality-adjusted life-years (QALYs) and savings of €2,397 per patient]. At a cost-effectiveness threshold of €30,000 per QALY gained, the probability that fidaxomicin was cost-effective was 96 %. For CDI patients treated with concomitant antibiotic therapy, fidaxomicin was the dominant treatment versus vancomycin (gain of 0.014 QALYs and savings of €1,452 per patient), with a probability that fidaxomicin was cost-effective of 94 %. For CDI patients with renal impairment, fidaxomicin was also dominant versus vancomycin (gain of 0.013 QALYs and savings of €1,432 per patient), with a probability that fidaxomicin was cost-effective of 96 %. Over a 1-year time horizon, when fidaxomicin is compared to vancomycin in CDI patients with cancer, treated with concomitant antibiotic therapy or with renal impairment, the use of fidaxomicin would be expected to result in increased QALYs for patients and reduced overall costs.