BACKGROUND: The aim of this study was to evaluate the protective effect of melatonin on ischemia-reperfusion syndrome. METHODS: Thirty-three adult male Wistar albino rats were randomized into three experimental groups of 11: Group C – control group with no ischemia or reperfusion. Groups I/R and I/R + M had 2.5 hours of ischemia and of two hours of reperfusion by means of clamping of the common femoral artery. All the animals received maintenance fluid with intraperitoneal (i.p) normal saline following general anesthesia. The animals of Group I/R + M were treated with i.p Melatonin (10 mg/kg) five minutes before reperfusion. At the end of reperfusion, samples were taken for histological evaluation and biochemical analysis. Parameters studied were biopsies of the soleus muscle, level of lactate, creatine phosphokinase (CPK), lactate dehydrogenase (LDH), sodium, potassium (K), calcium (Ca) and arterial blood gasometry. RESULTS: In I/R group, the levels of K, CPK increased dramatically contrast with groups C and IR+M (P<0.05). A significant decrease in HCO3 was found in I/R Group in comparison with Group IR+M and Group C (P<0.001). In Group IR+M, lactate level decreased dramatically compared to other groups (P<0.001). Histological injury in I/R + M was found to be less than in I/R group (P<0.05). There was no significant difference in PO2, pH, carbon dioxide, partial pressure of oxygen, Na, LDH, Ca and P in three groups (P>0.05). Histological change in the group C and group M didn’t differ significantly, but the difference in group I/R was significant compared to group C and IR+M (P<0.05). CONCLUSION: We suggest that melatonin has protective effect against I/R syndrome in blood and skeletal muscle and may reduce the morbidity following revascularization surgery in vascular trauma.