We describe the control of a hospital-wide vancomycin-resistant Enterococcus faecium (VRE) outbreak in a 2,000-bed university hospital located on three different sites in Clermont-Ferrand, France. From January 2004 to April 2007, 220 VRE cases were identified. Overall, 28 different wards had at least one case. All of the strains expressed a high level of resistance to vancomycin and to teicoplanin carried by the vanA gene. Pulsed-field gel electrophoresis (PFGE) analysis of the strains revealed that they were clonally related. Control measures consisted of implementing a strategy of VRE screening by rectal swab, reinforcing hand hygiene practices and taking contact precautions. Recommendations for a restricted use of specific antibiotics were sent to each physician. Alcohol-based handrubs were provided throughout the hospital and the staff underwent training for their use. Compliance with contact precautions, including the use of clean non-sterile gloves and single-use gowns, was reinforced. VRE cases were assigned systematically to a single-bed room. In October 2007, no new VRE carriage has been detected for 7 months and no clinical samples had been VRE-positive for 10 months. In conclusion, a hospital-wide VRE outbreak was successfully controlled by a strategy based on routine screening, the reinforcement of hand hygiene and taking barrier precautions.