Background: The ENIGMA trial was a prospective, randomized, multicenter study that evaluated the clinical consequences of including N2O in general anesthesia. Patients who were given a N2O-free anesthetic when undergoing major surgery for which the expected hospital stay was at least 3 days had lower rates of some postoperative complications. This suggests that, despite a higher consumption of potent inhalational agent, there could be a financial benefit when N2O is avoided in such settings. Methods: A retrospective cost analysis of the 2,050 patients recruited to the ENIGMA trial was performed. We measured costs from the perspective of an implementing hospital. Direct health care costs include the costs for maintaining anesthesia, daily medications, hospitalization, and complications. The primary outcome was the net financial savings from avoiding N2O in major noncardiac surgery. Comparisons between groups were analyzed using Student t test and bootstrap Methods. Sensitivity analyses were also performed. Results: Rates of some serious complications were higher in the N2O group. Total costs in the N2O group were 16,203 and in the N2O-free group 13,837, mean difference of 2,366 (95 CI: 841-3,891); P = 0.002. All sensitivity analyses retained a significant difference in favor of the N2O-free group (all P <0.005). Conclusions: Despite N2O reducing the consumption of more expensive potent inhalational agent, there were marked additional costs associated with its use in adult patients undergoing major surgery because of an increased rate of complications. There is no cogent argument to continue using N2O on the basis that it is an inexpensive drug.