OBJECTIVE: To determine the effect of arterial normobaric hyperoxia during cardiopulmonary bypass (CPB) on postoperative neurocognitive function. The authors hypothesized that arterial hyperoxia during CPB is associated with neurocognitive decline at 6 weeks after cardiac surgery. DESIGN: Retrospective study of patients undergoing cardiac surgery with CPB. SETTING: A university hospital. PARTICIPANTS: One thousand eighteen patients undergoing coronary artery bypass graft (CABG) or CABG + valve surgery with CPB who previously had been enrolled in prospective cognitive trials. INTERVENTIONS: A battery of neurocognitive measures was administered at baseline and 6 weeks after surgery. Anesthetic and surgical care was managed as clinically indicated. MEASUREMENTS AND MAIN RESULTS: Arterial hyperoxia was assessed primarily as the area under the curve (AUC) for the duration that PaO2 exceeded 200 mmHg during CPB and secondarily as the mean PaO2 during bypass, as a PaO2 = 300 mmHg at any point and as AUC>150 mmHg. Cognitive change was assessed both as a continuous change score and a dichotomous deficit rate. Multivariate regression accounting for age, years of education, baseline cognition, date of surgery, baseline postintubation PaO2, duration of CPB, and percent change in hematocrit level from baseline to lowest level during CPB revealed no significant association between hyperoxia during CPB and postoperative neurocognitive function. CONCLUSIONS: Arterial hyperoxia during CPB was not associated with neurocognitive decline after 6 weeks in cardiac surgical patients.