Toxic megacolon is a severe complication of Clostridium difficile infection (CDI) with a high percentage of mortality. The mainstay of treatment is currently represented by medical management, while surgical intervention is indicated in patients not improving after 2-3 days of antibiotic therapy. Generally metronidazole and vancomycin are administered as first-line treatment, but recently several cases of refractory C. difficile have made the treatment of this infection more difficult. Fidaxomicin is a narrow-spectrum oral macrocyclic antibiotic with excellent in vitro activity against C. difficile strains. We report the case of a woman admitted with a diagnosis of toxic megacolon complicating a C. difficile colitis not responding to standard antibiotic therapy.