Excessive haemodilution and the resulting anaemia during CPB is accompanied by a decrease in the total arterial oxygen content, which may impair tissue oxygen delivery. Hyperoxic ventilation has been proven to improve tissue oxygenation in different pathophysiological states of anaemic tissue hypoxia. The aim of this study was to examine the influence of arterial hyperoxaemia on tissue oxygenation during CPB. Records of patients undergoing isolated CABG with CPB were retrospectively reviewed. Patients with nadir haematocrit levels below 20% during CPB were included in the study. Tissue hypoxia was defined as hyperlactataemia (lactate >2.2 mmol/L) coupled with low ScVO₂ (ScVO₂ <70%) during CPB. One hundred patients with normoxaemia and 100 patients with hyperoxaemia were included in the study. Patients with hyperoxaemia had lower tissue hypoxia incidence than patients with normoxaemia (p<0.001). Compared with patients without tissue hypoxia, patients with tissue hypoxia had significantly lower PaO₂ values (p<0.001) and nadir haematocrit levels (p<0.001). Nadir haematocrit levels <18% (OR: 5.3; 95% CI: 2.67–10.6; p<0.001) and hyperoxaemia (OR: 0.28; 95% CI: 0.14–0.56; p<0.001) were independently associated with tissue hypoxia.