The objective of this study was to evaluate the efficacy and safety of fidaxomicin in the real-life clinical setting. This was a retrospective cohort of patients with Clostridium difficile infection (CDI) treated with fidaxomicin in 20 Spanish hospitals between July 2013 and July 2014. Clinical cure, 30-day recurrence, 30-day mortality, sustained cure, and factors associated with the failure to achieve sustained cure were analyzed. Of the 72 patients in the cohort 41 (56.9 %) had a fatal underlying disease. There were 44 (61.1 %) recurrent episodes and 26 cases (36.1 %) with a history of multiple recurrences. Most episodes were severe (26, 36 %) or severe-complicated (14, 19.4 %). Clinical cure rate was 90.3 %, recurrence rate was 16.7 % and three patients (4.2 %) died during the follow-up period. Sustained cure was achieved in 52 cases (72.2 %). Adverse events were reported in five cases (6.9 %). Factors associated with the lack of sustained cure were cardiovascular comorbidity (OR 11.4; 95 %CI 1.9-67.8), acute kidney failure (OR 7.4; 95 %CI 1.3-43.1), concomitant systemic antibiotic treatment (OR 6.2; 95 %CI 1.1-36.8), and C-reactive protein value at diagnosis (OR 1.2 for each 1 mg/dl increase; 95 %CI 1.03-1.3). Fidaxomicin is an effective and well tolerable treatment for severe CDI and for cases with elevated recurrence risk.