Background: Intravenous and inhalational anesthesia might have different associations with long-term outcome in cancer patients, with reports of adverse effects of inhalation anesthesia. However, the effects of anesthesia in patients with high-grade glioma (HGG) are not known. Methods: This study investigated 154 patients who received propofol and 140 patients who received sevoflurane for maintenance of anesthesia during HGG tumor resection. The primary outcomes were progression-free survival and overall survival. Results: Median progression-free survival was 10 months (interquartile range [IQR], 6 to 18) versus 11 months (IQR 6 to 20; P = 0.674), and median overall survival was 18 months (IQR, 11 to 39) versus 18 months (IQR, 10 to 44; P = 0.759) in patients maintained with propofol and sevoflurane, respectively. Higher preoperative Karnofsky performance status and postoperative chemotherapy were associated with a reduced hazard of tumor progression or death, whereas higher age-adjusted Charlson comorbidity index and longer duration of anesthesia were associated with an increased hazard of progression or death. World Health Organization tumor classification IV and incomplete tumor resection were associated with an increased hazard of tumor progression but not death. Anesthesia maintenance with sevoflurane increased the risk of death in patients with Karnofsky performance status <80 compared with propofol (hazard ratio, 1.66; 95% confidence interval, 1.08-2.57; P =0.022). Conclusions: Compared with maintenance of anesthesia with propofol, sevoflurane did not worsen progression-free or overall survival in patients with HGG undergoing tumor resection. However, propofol might be beneficial in patients with poor preoperative Karnofsky performance status. © 2019 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.