IMPORTANCE Intraoperative electroencephalogram (EEG) waveform suppression, often suggesting excessive general anesthesia, has been associated with postoperative delirium. OBJECTIVE To assess whether EEG-guided anesthetic administration decreases the incidence of postoperative delirium. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial of 1232 adults aged60years and older undergoing major surgery and receiving general anesthesia at Barnes-Jewish Hospital in St Louis. Recruitmentwas from January 2015 toMay 2018, with follow-up until July 2018. INTERVENTIONS Patients were randomized 1:1 (stratified by cardiac vs noncardiac surgery and positive vs negative recent fall history) to receive EEG-guided anesthetic administration (n = 614) or usual anesthetic care (n = 618). MAIN OUTCOMES AND MEASURES The primary outcomewas incident delirium during postoperative days 1 through 5. Intraoperative measures included anesthetic concentration, EEG suppression, and hypotension. Adverse events included undesirable intraoperative movement, intraoperative awareness with recall, postoperative nausea and vomiting, medical complications, and death. RESULTS Of the 1232 randomized patients (median age, 69 years [range, 60to 95]; 563women [45.7%]), 1213 (98.5%)were assessed for the primary outcome. Delirium during postoperative days 1 to 5 occurred in 157 of 604patients (26.0%)in the guided group and 140 of 609 patients (23.0%)in the usual care group (difference, 3.0%[95%CI, -2.0%to 8.0%]; P = .22). Median end-tidal volatile anesthetic concentrationwas significantly lower in the guided group than the usual care group (0.69 vs0.80minimum alveolar concentration; difference, -0.11 [95%CI, -0.13 to -0.10), and median cumulative time with EEGsuppressionwas significantly less (7 vs 13 minutes; difference, -6.0[95%CI, -9.9 to -2.1]). Therewas no significant difference between groups in the median cumulative time with mean arterial pressure below60mmHg (7 vs 7 minutes; difference,0.0[95%CI, -1.7 to 1.7]). Undesirablemovement occurred in 137 patients (22.3%) in the guided and 95 (15.4%) in the usual care group.Nopatients reported intraoperative awareness. Postoperative nausea and vomitingwas reported in 48 patients (7.8%) in the guided and 55 patients (8.9%) in the usual care group. Serious adverse eventswere reported in 124 patients (20.2%) in the guided and 130 (21.0%)in the usual care group. Within 30 days of surgery, 4 patients (0.65%) in the guided group and 19 (3.07%) in the usual care group died. CONCLUSIONS AND RELEVANCE Among older adults undergoing major surgery, EEG-guided anesthetic administration, compared with usual care, did not decrease the incidence of postoperative delirium. This finding does not support the use of EEG-guided anesthetic administration for this indication. © 2019 American Medical Association.