AIMS: Systemic inflammation and increased activity of atrial NOX2-containing NADPH oxidases have been associated with the new onset of atrial fibrillation (AF) after cardiac surgery. In addition to lowering LDL-cholesterol, statins exert rapid anti-inflammatory and antioxidant effects, the clinical significance of which remains controversial. METHODS AND RESULTS: We first assessed the impact of cardiac surgery and cardiopulmonary bypass (CPB) on atrial nitroso-redox balance by measuring NO synthase (NOS) and GTP Cyclohydrolase -1 (GCH-1) activity, biopterin content, and superoxide production in paired samples of the right atrial appendage obtained before (PRE) and after CPB and reperfusion (POST) in 116 patients. The effect of perioperative treatment with atorvastatin (80 mg once daily) on these parameters, blood biomarkers and the postoperative atrial effective refractory period (AERP) was then evaluated in a randomized, double-blind, placebo-controlled study in 80 patients undergoing cardiac surgery on CPB.CPB and reperfusion led to a significant increase in atrial superoxide production (74% CI, 71-76%, n = 46 paired samples, P < 0.0001) and a reduction in atrial tetrahydrobiopterin (BH4) (34% CI, 33-35%, n = 36 paired samples, P < 0.01), and in GCH-1 (56% CI, 55-58%, n = 26 paired samples, P < 0.001) and NOS activity (58% CI, 52-67%, n = 20 paired samples, P < 0.001). Perioperative atorvastatin treatment prevented the effect of CPB and reperfusion on all parameters but had no significant effect on the postoperative right AERP, troponin release, or NT-pro BNP after cardiac surgery. CONCLUSIONS: Perioperative statin therapy prevents post-reperfusion atrial nitroso-redox imbalance in patients undergoing on-pump cardiac surgery but has no significant impact on postoperative atrial refractoriness, perioperative myocardial injury, or markers of postoperative LV function.Clinical Trial Registration information: https://clinicaltrials.gov/ct2/show/NCT01780740. TRANSLATIONAL PERSPECTIVE: Increased atrial ROS production is associated with both incident and prevalent AF, with experimental findings suggesting it may have a causal role in AF induction and AF-induced electrical remodelling. Statin therapy causes a reduction in myocardial and vascular ROS production and as such it may prevent the new onset of AF after cardiac surgery. In patients undergoing on-pump cardiac surgery, we show that perioperative administration of statins prevents myocardial nitroso-redox imbalance after reperfusion without affecting atrial refractoriness or perioperative myocardial injury. These findings suggest that targeting myocardial nitroso-redox imbalance would be unlikely to prevent postoperative complications in patients undergoing on-pump cardiac surgery.