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The Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia (ENIGMA)-II trial randomly assigned 7,112 noncardiac surgery patients at risk of perioperative cardiovascular events to 70% N2O or 70% N2 groups. The aim of this follow-up study was to determine the effect of nitrous oxide on a composite primary outcome of death and major cardiovascular events at 1 yr after surgery.One-year follow-up was conducted via a medical record review and telephone interview. Disability was defined as a Katz index of independence in activities of daily living score less than 8. Adjusted odds ratios and hazard ratios were calculated as appropriate for primary and secondary outcomes.Among 5,844 patients evaluated at 1 yr, 435 (7.4%) had died, 206 (3.5%) had disability, 514 (8.8%) had a fatal or nonfatal myocardial infarction, and 111 (1.9%) had a fatal or nonfatal stroke during the 1-yr follow-up period. Exposure to nitrous oxide did not increase the risk of the primary outcome (odds ratio, 1.08; 95% CI, 0.94 to 1.25; P = 0.27), disability or death (odds ratio, 1.07; 95% CI, 0.90 to 1.27; P = 0.44), death (hazard ratio, 1.17; 95% CI, 0.97 to 1.43; P = 0.10), myocardial infarction (odds ratio, 0.97; 95% CI, 0.81 to 1.17; P = 0.78), or stroke (odds ratio, 1.08; 95% CI, 0.74 to 1.58; P = 0.70).These results support the long-term safety of nitrous oxide administration in noncardiac surgical patients with known or suspected cardiovascular disease.