Tacrolimus (FK-506) is a powerful immunosuppressive agent that modulates neutrophil infiltration during inflammation. In this study, we sought to investigate the effects of melatonin on malondialdehyde (MDA), nitric oxide (NO), interleukin (IL)-6, and tumor necrosis factor-alpha (TNF-alpha) to oppose the negative effects of the immunosupressant FK-506. Group A was sham; group B, tacrolimus (1 mg/kg/d subcutaneously); and Group C received tacrolimus (1 mg/kg/d plus melatonin). All tissues underwent histopathologic examination. The MDA level in group B increased 53% compared with the sham group (P < .001); in group C, the MDA level decreased 1.6% compared with group B (P > .05). While TNF-alpha in group B increased 68.8% compared with the sham group (P < .001) and in group C it decreased 63.5% compared with the sham group. The IL-6 level in group B increased 81%; in group C, it decreased 13% compared with group B. NO levels in group B increased 48% compared with the sham group and increased by 15% in group B compared with group C. Thus melatonin may serve as a protective agent against the side effects of tacrolimus.