Background: The military is rapidly moving into a battlespace in which prolonged holding times in the field are probable. Ketamine provides hemodynamic support and has analgesic properties, but the safety of prolonged infusions is unclear. We compare in-hospital mortality between intubated burn intensive care unit (ICU) patients receiving prolonged ketamine infusion lasting =7 days or until death versus controls. Methods: We conducted a before/after cohort study of patients undergoing admission to a burn ICU with intubation within the first 24 hours as part of treatment for thermal burns. In January 2012, this ICU implemented a novel continuous ketamine infusions protocol. We performed a preintervention and postintervention cohort analysis. Results: We identified 2394 patients meeting our inclusion criteria-475 in the ketamine group and 1919 in the control group. Regarding burn total body surface area (TBSA) involvement, there were 1533 in the <10% group, 586 in the 11-30% group, and 281 in the >31% group. The median number of ventilator-free days within the first 30 days did not vary significantly between the ketamine group and the control group: 8.5 days (interquartile range [IQR] 1-16 days) versus 8 days (IQR 3-13 days, p = .442). Subjects receiving ketamine had higher mortality rates: 59.4% (n = 117) versus 40.6% (n = 80, p < .001), with an odds ratio for in-hospital mortality of 7.51 (95% CI 5.53-10.20, p < .001). When controlling for TBSA category, ventilator days and vasopressor administration, there was no association between ketamine and in-hospital mortality (0.66, 0.41-1.05, p = .08). Conclusions: When controlling for confounders, we found no difference in in-hospital mortality between the prolonged ketamine infusion recipients versus non-recipients.