During and after coronary artery bypass grafting (CABG), oxidative stress occurs. Finding an effective way to improveantioxidant response is important in CABG surgery. It has been shown that patients with coronary heart disease have a low Melatonin production rate. The present study aimed to investigate the effects ofMelatoninon nuclear erythroid 2-related factor 2(Nrf2) activity in patients undergoing CABG surgery. Thirty volunteers undergoing CABG were randomized to receive 10 mg oral Melatonin (Melatonin group, ) or placebo (placebo group, ) before sleeping for 1 month before surgery. The activatedNrf2 was measured twice by DNA-based ELISA method in the nuclear extract of peripheral blood mononuclear cells of patients before aortic clumps and 45 minutes after CABG operation. Melatonin administration was associated with a significantincrease in both plasma levels of Melatonin and Nrf2 concentration in Melatonin group compared to placebo group, respectively ( pmol/L, versus pmol/L, , ). The findings of the present study provide preliminary data suggesting that Melatoninmay play a significant role in the potentiation of the antioxidant defense and attenuate cellular damages resulting from CABG surgery via theNrf2 pathway.