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Objective: To describe a Klebsiella pneumoniae carbapenemase (KPC)-producing carbapenem-resistant Enterobacteriaceae (CRE) outbreak and interventions to prevent transmission., Design, Setting, and Patients: Epidemiologic investigation of a CRE outbreak among patients at a long-term acute care hospital (LTACH)., Methods: Microbiology records at LTACH A from March 2009 through February 2011 were reviewed to identify CRE transmission cases and cases admitted with CRE. CRE bacteremia episodes were identified during March 2009-July 2011. Biweekly CRE prevalence surveys were conducted during July 2010-July 2011, and interventions to prevent transmission were implemented, including education and auditing of staff and isolation and cohorting of CRE patients with dedicated nursing staff and shared medical equipment. Trends were evaluated using weighted linear or Poisson regression. CRE transmission cases were included in a case-control study to evaluate risk factors for acquisition. A real-time polymerase chain reaction assay was used to detect the bla(KPC) gene, and pulsed-field gel electrophoresis was performed to assess the genetic relatedness of isolates., Results: Ninety-nine CRE transmission cases, 16 admission cases (from 7 acute care hospitals), and 29 CRE bacteremia episodes were identified. Significant reductions were observed in CRE prevalence (49% vs. 8%), percentage of patients screened with newly detected CRE (44% vs. 0%), and CRE bacteremia episodes (2.5 vs. 0.0 per 1,000 patient-days). Cases were more likely to have received β-lactams, have diabetes, and require mechanical ventilation. All tested isolates were KPC-producing K. pneumoniae, and nearly all isolates were genetically related., Conclusion: CRE transmission can be reduced in LTACHs through surveillance testing and targeted interventions. Sustainable reductions within and across healthcare facilities may require a regional public health approach.