Summary Oxidative stress underlies postoperative atrial fibrillation and electrophysiological remodelling associated with rapid atrial pacing. An increasing body of evidence indicates that the formation of reactive oxygen species (ROS) released following extracorporeal circulation are involved in the structural and functional myocardial impairment derived from the ischemia–reperfusion cycle. ROS behave as intracellular messengers mediating pathological processes, such as inflammation, apoptosis and necrosis, thereby participating in the pathophysiology of atrial fibrillation. Thus, increased superoxide ( O 2 · - ) production has been found in isolated atrial cardiomyocytes from patients with atrial fibrillation. Therefore, it seems reasonable to assume that the reinforcement of the antioxidant defense system should protect the heart against functional alterations in the cardiac rhythm. On this line, antioxidant enzyme induction through in vivo exposure to moderate concentration of ROS is associated with a reduction in the susceptibility of myocytes to ROS-induced injury. This response could be due to a prevailing effect of survival over apoptotic pathway. Previously, tissue preconditioning caused by prior exposure to an ischemia/reperfusion cycle has been successfully applied in experimental models and clinical settings associated with oxidative damage by ROS. However, such hypoxic preconditioning method is harmful to be applied to many clinical conditions associated with oxidative stress. In turn, experimental studies have revealed that non-enzymatic antioxidants produce a significant functional amelioration in cardiomyocytes subjected to an oxidative challenge. Moreover, clinical studies with patients scheduled for primary coronary artery bypass graft surgery had a reduced incidence of postoperative atrial fibrillation. We present the hypothesis of non-hypoxic preconditioning based on the association of pretreatment with n-3 polyunsaturated fatty acids followed by ascorbate plus α-tocoferol supplementation diminishes the incidence of postoperative atrial fibrillation in patients subjected to cardiac surgery with extracorporeal circulation.