Background: Nephrotoxicity is an important side effect of FK506 and oxidative stress has been considered as one of the possible mechanisms. The present investigation examines the ability of melatonin to protect against FK506-induced renal oxidative stress. Methods: Thirty rats were divided into 3 groups (n = 10 each group). Group A was the sham group. Group B received 14 days FK506 (5 mg/kg/d, intraperitoneally [i.p.]) and group C received FK506 (5 mg/kg/d, i.p.) together with melatonin (4 mg/kg, i.p.) for 14 days. Kidney tissues were harvested to determine the tissue levels of malondialdehyde (MDA), total nitrite and nitric oxide (NO), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6). Results: In group C, the levels of TNF-α, IL-6, and NO were lower than in the group B (P <.01, P <.03, and P <.04, respectively) and although MDA levels were lower than in group B, the differences were not statistically significant (P <.05). Conclusion: These results suggest that melatonin has protective effect against FK506-induced renal oxidative stress. © The Author(s) 2011.