© 2022 Tehran University of Medical Sciences. Published by Tehran University of Medical Sciences.Background: In cardiac surgery, supraphysiological oxygen levels are frequently applied perioperatively. In this study, we examined the postoperative effect of perioperative hyperoxemia in cardiac surgery. Methods: All patients who underwent mitral valve replacement via the standard sternotomy method between 2010 and 2021 were analyzed by scanning the hospital data system. The patients were divided into 2 groups: the hyperoxemic group (partial pressure of oxygen/fraction of inspired oxygen [PaO2/FiO2] >500 mmHg) (Group I) and the normoxemic group (300 mmHg < PaO2/FiO2 < 500 mmHg) (Group II) according to the mean of 3 PaO2/FiO2 values calculated by using 3 PaO2 and 3 FiO2 levels. Postoperative complications, the mechanical ventilation time, the need for noninvasive mechanical ventilator support, the length of intensive care unit (ICU) stay, the hospitalization period, and the mortality rate of the groups were compared. Results: A total of 78 patients were included in the study, and 53 of the patients (67.9%) were female. The mean age of the patients was 58.89±12.60 years. The total mechanical ventilation time was significantly higher in the hyperoxemic group than in Group II (P<0.001) (18.18±12.90 h and 11.45±7.85 h, respectively). The amount of postoperative bleeding was significantly higher in Group I (P=0.003) (539.47±201.74 mL and 417.50±186.93 mL, respectively). The total amount of blood products administered during surgery and ICU stay was higher in Group I (P=0.041) (3.55±1.59 units and 2.87±1.89 units, respectively). Conclusion: We observed that the group with hyperoxemia during cardiopulmonary bypass had a higher amount of postoperative bleeding and the need for transfusion, as well as a longer duration of mechanical ventilation and intensive care.