The treatment of unresponsive or recurrent Clostridium difficile infection can be challenging. Compared to vancomycin, fidaxomicin has demonstrated significantly lower rates of first and second recurrences. However, there are limited data available for treating patients with multiple episodes of recurrence. We report on 8 recent patients treated with fidaxomicin after failing or not responding to at least 2 previous therapies. The treatment of 5 outpatients with mild to moderate disease and 3 inpatients with severe disease ultimately was changed to fidaxomicin and achieved clinical response, defined as resolution of diarrhea at the end of fidaxomicin therapy for which no further treatment was required. Follow-up ranged from 60 days to 21 months. Only one patient experienced recurrence, but sustained clinical response was achieved with a second course of fidaxomicin. Although further research is warranted, fidaxomicin may be useful in the treatment of Clostridium difficile infection in patients unresponsive to multiple regimens or with multiple recurrences.