We investigated the changes in the serum levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, the pro-inflammatory cytokines, and the possible effect of melatonin on the modulation of these inflammatory molecules after renal ischemia reperfusion (IR). The study was carried out in the laboratory of Department of Pharmacology. Forty-six male Wistar albino rats were divided into five groups as control (n = 6), positive control (n = 4), sham (n = 12), renal IR (n = 12), and renal IR melatonin (n = 12). After 1 h renal pedicle occlusion, the blood samples were taken for the measurement of cytokine levels at second hour of the reperfusion. The rats were sacrificed after 24 h of reperfusion for histopathological evaluation. Melatonin or vehicle was administrated to IR rats. Lipopolysaccharide (LPS) was administered to the positive control group and the blood was taken at fourth hour. Serum TNF-alpha levels increased significantly in renal IR and LPS groups. Serum IL-6 levels were not different from control except the LPS group. There was no significant correlation between the serum TNF-alpha levels and the histopathological score after renal IR. Melatonin treatment reversed the increase of serum TNF-alpha levels and histopathological injury in renal tissue after renal IR. Melatonin may have a protective effect by reducing the serum level of TNF-alpha in renal IR.