BACKGROUND: Sleep deprivation resulting from night shifts, is a major cause of burnout among physicians. Exogenous melatonin may improve sleep quality in night-shift workers. The study aims to compare the effectiveness of melatonin versus placebo on sleep efficiency in emergency medicine (EM) residents. METHODS: A randomized, double-blind, replicated crossover trial was performed on EM residents. This study consisted of 4 phases within a month with intervention periods of 2 nights and washouts of 6 days. In our study, EM residents had nine-hour shifts on 6 consecutive days, 2 mornings, 2 evenings and 2 nights and then 2 days off. At the end of shifts' cycle, 24 EM residents were given 3 mg melatonin or placebo (12 in each arm of the study) for 2 consecutive nights after the second night shift with crossover to the other arm after a six-day off drug. This crossover intervention was repeated for two more another time. Finally, we created 48 cases and comparisons in each arm. Different items related to sleep quality were assessed and compared both within the same group and between the two groups. RESULTS: In the melatonin group, daytime sleepiness (calculated by Karolinska Sleep Scale) had a significant reduction after taking the second dose of drug (P=0.003) but the same result was not observed when comparing the 2 groups. Mood status (calculated by Profile of Mood States) showed no remarkable difference between the 2 groups. CONCLUSION: Melatonin might have a limited benefit on sleep quality in EM residents working night shifts.