Objective. To devise a local strategy for eradication of a hospital-wide outbreak caused by carbapenem-resistant Klebsiella pneumoniae (CRKP). Design. Quasi-experimental, before-and-after, interrupted time-series study. Setting. A 1,000-bed tertiary-care university teaching hospital. Methods. Retrospectively, all relevant data were collected from the medical records of patients with CRKP infections from May 2006 through April 2007, the preintervention period. From May 1, 2007, through May 1, 2010, the postintervention period, the intervention was applied and prospectively followed. The 5 key elements of this strategy were an emergency department flagging system, the building of a cohort ward, the eradication of clusters, environmental and personnel hand cultures, and a carbapenem-restriction policy. The demographic and clinical parameters of patients colonized by and/or infected with CRKP were collected from medical records. Results. A total of 10,680 rectal cultures were performed for 8,376 patients; 433 (5.16%) and 370 (4.4%) were CRKP-colonized and CRKP-infected patients, respectively, and 789 (98%) of 803 patients were admitted to the CRKP cohort ward. The CRKP infection density was reduced from 5.26 to 0.18 per 10,000 patient-days (P ≤.001), and no nosocomial CRKP infections were diagnosed. Twenty-three percent of environmental cultures were found to be positive. Meropenem use was reduced from 283±70.92 to 118±74.32 defined daily doses per 1,000 patient-days (P ≤.001). conclusion. This intervention produced an enormous impact on patient location, surveillance cultures, and antibiotic policies and a massive investment in infection control resources.