Carbapenem-resistant Enterobacteriaceae (CRE) are an urgent antibiotic resistant threat. Only sporadic reports of CRE in companion animals have been described. Our objective was to identify risk factors associated with the acquisition of a blaNDM-5 CR-Escherichia coli strain as part of an outbreak investigation at a tertiary veterinary hospital in the United States. A matched case–control study was conducted among companion animals admitted during July 1, 2018, through June 30, 2019. The 15 identified blaNDM-5 CR-E coli cases were matched 1:2 with controls (culture negative for blaNDM-5 CR-E coli) based on species and number of days of hospitalization before bacterial culture sample collection. The association between exposure to various procedures and hospital services and the acquisition of blaNDM-5 CR-E. coli was assessed through conditional logistic regression. Case patients had significantly higher odds of exposure to the anesthesia service (odds ratio [OR] = 12.8, P = .017), the surgical service (OR = 4.0, P = .046), and to endotracheal intubation (OR = 10.0, P = .03). Veterinary hospitals should be aware of the potential for transmission of CRE via anesthetic and surgical procedures, especially those that require the placement of endotracheal tubes.