Surgery for abdominal aortic aneurysm is associated with elevated oxidative stress. As an antioxidant in animal and human studies, melatonin has the potential of ameliorating some of this oxidative stress, but melatonin has never been administered to adults during surgery for the purpose of reducing oxidative damage. The aim of this pilot study was to evaluate the safety of various doses of melatonin administered during or after surgery and to monitor the changes in biomarkers of oxidative stress and inflammation during the pre-, intra- and postoperative period. Six patients undergoing aortic surgery received 10 (n=2), 30 (n=2) or 60 (n=2) mg melatonin intravenously in the intraoperative phase and 10 mg orally for three nights after surgery. Patients were monitored for hemodynamic parameters during and after surgery. Any unexpected events during the hospitalization were registered. Blood samples were collected preoperatively and at 5 min, 6 hrs and 24 hrs after clamp removal or after re-circulation of the first leg and the samples were analysed for malondialdehyde (MDA), ascorbic acid (AA), dehydroascorbic acid (DHA) and interleukin-6 (IL-6). Troponin I (TpI) and C-reactive protein (CRP) were also measured for four days after surgery. Melatonin administration did not change hemodynamic parameters (mean arterial pressure or pulse rate) during surgery (P=0.499 and 0.149, respectively), but oxidative stress parameters (MDA and AA) decreased significantly (P=0.014 and 0.001, respectively). There was a significant increase in the inflammatory parameters (IL-6 and CRP) (P=0.001 and 0.001, respectively) and an increase in TpI (P=0.009) as a consequence of surgery. These were not influenced by melatonin treatment. Treatment of patients undergoing major aortic surgery with melatonin intravenously up to 60 mg in the intraoperative phase was safe and without complications. Melatonin may decrease oxidative damage resulting from surgery, but randomized clinical trials are required before definitive conclusions can be drawn regarding the clinical benefit of melatonin in surgical situations.