Fidaxomicin, a macrocyclic antibiotic, selectively kills Clostridioides difficile and reduces C. difficile infection (CDI) recurrence compared with vancomycin, but some studies and guidelines report fidaxomicin as being less cost-effective. The aim of this study was to compare the cost-effectiveness and budget impact of fidaxomicin versus vancomycin or metronidazole for treating CDI in a real-world UK setting. Data were retrospectively collected from medical records of 86 patients with CDI treated with vancomycin or metronidazole at a single UK hospital between April 2011 and March 2012, and prospectively from 62 patients with CDI treated with fidaxomicin between August 2012 and July 2013. CDI cases were matched by age, financial year, and healthcare resource use to control cases. CDI recurrence rates were lower with fidaxomicin (6.5%) than vancomycin/metronidazole (19.8%). An estimated 12 additional recurrent CDIs were prevented with fidaxomicin treatment. Patients with CDI had significantly higher healthcare costs than those without CDI, with a mean excess spend of GBP 10,748 and GBP 17,451 per patient in the fidaxomicin (p = 0.015) and vancomycin/metronidazole cohorts (p < 0.001), respectively. A second CDI was associated with mean excess costs of GBP 8373 and GBP 20,249 per patient in the fidaxomicin and vancomycin/metronidazole cohorts, respectively. Despite higher fidaxomicin drug costs, overall cost savings were estimated at GBP 140,292 (GBP 2125 per CDI). In this real-world study, first-line CDI treatment with fidaxomicin reduced healthcare costs versus vancomycin/metronidazole, consistent with previous studies.