Background: The hypothesis is that a hypoxic-hyperoxic preconditioning (HHP) is associated with a protective effect on myocardial function by reducing endothelial damage and a beneficial effect on postoperative outcome in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Methods: Patients (n=120) were randomly assigned to an HHP and a control group. A safe inhaled oxygen fraction for the hypoxic preconditioning phase (10-14% oxygen for 10 minutes) was determined by measuring the anaerobic threshold. At hyperoxic phase, 75-80% oxygen fraction was used during 30 minutes. Results: The cumulative frequency of postoperative complications was 14 (23.3%) in the HHP vs 23 (41.1%), p=0.041. The nitrate decreased after surgery by up to 20% in the HHP group and up to 38% in the control group. Endothelin-1 and nitric oxide metabolites were stable in HHP but remained low more than 24 h in control group. The endothelial damage markers appeared to be predictors of postoperative complications. Conclusion: The HHP with individual parameters based on the anaerobic threshold is a safe procedure, it can reduce the frequency of postoperative complications. The endothelial damage markers appeared to be predictors of postoperative complications.