Objectives To determine whether high perioperative inspired oxygen fraction (FiO2) compared with low FiO2 has more deleterious postoperative clinical outcomes in patients undergoing non-thoracic surgery under general anesthesia. Design Meta-analysis of randomized controlled trials. Setting Operating room, postoperative recovery room and surgical ward. Patients Surgical patients under general anesthesia. Intervention High perioperative FiO2 (≥0.8) vs. low FiO2 (≤0.5). Measurements The primary outcome was mortality within 30 days. Secondary outcomes were pulmonary outcomes (atelectasis, pneumonia, respiratory failure, postoperative pulmonary complications [PPCs], and postoperative oxygen parameters), intensive care unit (ICU) admissions, and length of hospital stay. A subgroup analysis was performed to explore the treatment effect by body mass index (BMI). Main results Twenty-six trials with a total 4991 patients were studied. The mortality in the high FiO2 group did not differ from that in the low FiO2 group (risk ratio [RR] 0.91, 95% confidence interval [CI] 0.42–1.97, P = 0.810). Nor were there any significant differences between the groups in such outcomes as pneumonia (RR 1.19, 95% CI 0.74–1.92, P = 0.470), respiratory failure (RR 1.29, 95% CI 0.82–2.04, P = 0.270), PPCs (RR 1.05, 95% CI 0.69–1.59, P = 0.830), ICU admission (RR 0.94, 95% CI 0.55–1.60, P = 0.810), and length of hospital stay (mean difference [MD] 0.27 d, 95% CI -0.28–0.81, P = 0.340). The high FiO2 was associated with postoperative atelectasis more often (risk ratio 1.27, 95% CI 1.00–1.62, P = 0.050), and lower postoperative arterial partial oxygen pressure (MD −5.03 mmHg, 95% CI -7.90– -2.16, P 30 kg/m2, these parameters were similarly affected between the groups. Conclusions The use of high FiO2 compared to low FiO2 did not affect the short-term mortality, although it may increase the incidence of atelectasis in adult, non-thoracic patients undergoing surgical procedures. Nor were there any significant differences in other secondary outcomes.