ABSTRACT: INTRODUCTION: As data from Clostridium difficile infection (CDI) in intensive care unit (ICU) are still scarce, our objectives were to assess the morbidity and mortality of ICU-acquired CDI. METHODS: We compared patients with ICU-acquired CDI (watery or unformed stools occurring ≥ 72 hours after ICU admission with a stool sample positive for C. difficile toxin A or B) with two groups of controls hospitalized at the same time in the same unit. The first control group comprised patients with ICU-acquired diarrhea occurring ≥ 72 hours after ICU admission with a stool sample negative for C. difficile and for toxin A or B. The second group comprised patients without any diarrhea. RESULTS: Among 5,260 patients, 512 patients developed one episode of diarrhea. Among them, 69 (13.5%) had a CDI; 10 (14.5%) of them were community-acquired, contrasting with 12 (17.4%) that were hospital-acquired and 47 (68%) that were ICU-acquired. A pseudomembranous colitis was associated in 24/47 (51%) ICU patients. The median delay between diagnosis and metronidazole administration was one day (25th Quartile; 75th Quartile (0; 2) days). The case-fatality rate for patients with ICU-acquired CDI was 10/47 (21.5%), as compared to 112/443 (25.3%) for patients with negative tests. Neither the crude mortality (cause specific hazard ratio; CSHR = 0.70, 95% confidence interval; CI 0.36 to 1.35, P = 0.3) nor the adjusted mortality to confounding variables (CSHR = 0.81, 95% CI 0.4 to 1.64, P = 0.6) were significantly different between CDI patients and diarrheic patients without CDI. Compared to the general ICU population, neither the crude mortality (SHR = 0.64, 95% CI 0.34 to 1.21, P = 0.17), nor the mortality adjusted to confounding variables (CSHR = 0.71, 95% confidence interval (CI) 0.38 to 1.35, P = 0.3), were significantly different between the two groups. The estimated increase in the duration of stay due to CDI was 8.0 days ± 9.3 days, (P = 0.4) in comparison to the diarrheic population, and 6.3 days ± 4.3 (P = 0.14) in comparison to the general ICU population. CONCLUSIONS: If treated early, ICU-acquired CDI is not independently associated with an increased mortality and impacts marginally the ICU length of stay.