This study describes the course of an OXA-48-producing Enterobacteriaceae (OPE) outbreak that started in March 2012 in a neonatal intensive care unit (NICU) in Jerusalem, Israel. During the peak of the outbreak (January to August 2012), there were 49 patients who had proven or suspected acquisition of OPE in the NICU, including 16 with invasive infections, out of a total of 156 patients who were hospitalized during that period. Three children hospitalized in the pediatric ICU were identified as carriers of OPE. Three patients with a previous stay in the affected NICU were identified as OPE carriers upon admission to another hospital. The Ministry of Health was notified and then intervened in July 2012. Intervention included cohorting colonized patients, conducting frequent rectal-culture surveillance, and improving the implementation of infection control practices. As a result, the incidence of OPE acquisition declined to 5 cases in the first 4 months, followed by no new cases in the next 3 months. Thirty-one patient-unique isolates were available for analysis: 29 Klebsiella pneumoniae isolates, all belonging to a single clone (sequence type 39 [ST39]), and 2 isolates from Enterobacter cloacae. All isolates possessed the blaOXA-48 and blaCTX-M-14 genes, which are located on the same plasmid. This plasmid, similar to the global blaOXA-48-harboring vector, has now acquired blaCTX-M-14, leading to resistance to all β-lactam agents.