BACKGROUND:: The usefulness of the oxygen reserve index (ORi) in reducing hyperoxemia remains unclear. We designed this study to investigate whether fraction of inspired oxygen (FiO2) adjustment under a combination of ORi and peripheral oxygen saturation (SpO2) guidance can reduce intraoperative hyperoxemia compared to SpO2 alone. METHODS:: In this prospective, double-blind, randomized controlled study, we allocated patients scheduled for laparoscopic gastrectomy to the SpO2 group (FiO2 adjusted to target SpO2 ≥ 98%) or the ORi-SpO2 group (FiO2 adjusted to target 0 < 0 ORi < .3 and SpO2 ≥ 98%). The ORi, SpO2, FiO2, arterial partial pressure of oxygen (PaO2), and incidence of severe hyperoxemia (PaO2 ≥ 200 mm Hg) were recorded before and 1, 2, and 3 hours after surgical incision. Data from 32 and 30 subjects in the SpO2 and ORi-SpO2 groups, respectively, were analyzed. RESULTS:: PaO2 was higher in the SpO2 group (250.31 ± 57.39 mm Hg) than in the ORi-SpO2 group (170.07 ± 49.39 mm Hg) 1 hour after incision (P < .001). PaO2 was consistently higher in the SpO2 group than in the ORi-SpO2 group, over time (P = .045). The incidence of severe hyperoxemia was higher in the SpO2 group (84.4%) than in the ORi-SpO2 group (16.7%, P < .001) 1 hour after incision. Higher FiO2 was administered to the SpO2 group [52.5 (50–60)] than the ORi-SpO2 group [40 (35–50), P < .001] 1 hour after incision. SpO2 was not different between the 2 groups. CONCLUSION:: The combination of ORi and SpO2 guided FiO2 adjustment reduced hyperoxemia compared to SpO2 alone during laparoscopic gastrectomy.