We have evaluated the hypnotic effect of perioperative sublingual melatonin administration in 50 adult patients undergoing major surgery in a prospective, randomized, double blind, placebo-controlled study. 25 patients were given sublingual melatonin and 25 patients were given saline, approximately 100 minutes before a standard anaesthetic and again at 23:00 hours on the day of the operation and on the following day. Sedation and anxiety were quantified before, and 10, 30, 60, and 90 min after premedication, and 15, 30, 60, and 90 min after admission to the recovery room. Blood samples were taken for evaluation of melatonin and stress hormones “cortisol and epinephrine” concentrations. On the 3rd day postoperatively, patients were asked about satisfaction with the premedication, sleep disruption and any of the suspected side effects of melatonin. Patients who received melatonin had a significant decrease in anxiety levels and increase in levels of sedation before operation compared with controls. Melatonin was effective in decreasing perioperative levels of cortisol and epinephrine compared to placebo. Patients in the placebo group had a decreased nocturnal secretion of melatonin during the first 48 hours postoperatively while patients received melatonin had a better circadian rhythm. Patients received melatonin were more satisfied with premedication without significant differences in the side effects as compared to placebo. It can be concluded that melatonin can be used safely and effectively for premedication and postoperatively as a hypnotic in patients undergoing major surgery.