In 2009, following the occurrence of several outbreaks of carbapenemase-producing Enterobacteriaceae (CPE), a programme for controlling the spread of CPE was implemented in the 38 hospitals of the Assistance Publique-Hôpitaux de Paris, a 21,000-bed institution. This programme included recommendations to isolate, and screen for CPE, patients previously hospitalised abroad, and bundled measures to control cross transmission (barrier precautions, dedicated staff and screening of contact patients). From 2004 to 2012, 140 CPE index cases were identified, 17 leading to outbreaks. After application of the programme, in spite of an increase in the number of CPE index cases epidemiologically linked with a recent stay or hospitalisation abroad, the proportion of cases followed by outbreaks, which was 40% (4/10) before 2009, decreased to 10% (13/130) (p=0.02), and the proportion of secondary cases among all CPE cases decreased from 69% (22/32) to 23% (38/168), (p<0.001). The number of secondary cases varied significantly depending on the speed and strength of the measures implemented around the CPE index case: quick (within two days of patient admission at the hospital) setting of nursing staff dedicated to the patient, quick setting of simple barrier precautions, or delayed measures of control (p=0.001). A sustained and coordinated strategy can lead to control CPE at the level of a large regional multi-hospital institution in a country where CPE are at an emerging stage.