Melatonin is an important antioxidant, and through its anti-inflammatory effects it can control immune responses, oxidative stress, and defense cell infiltration. Periodontitis is a disease of the oral cavity and the generation of free radicals is an important consideration in this disease. Therefore, we examined the immune-modulatory and antioxidant roles of melatonin in the treatment of periodontitis. In all, 30 male Wistar rats were randomly divided into three groups: the control group, the periodontitis-induced (PED) group, and the periodontitis+melatonin treatment (MEL+PED) group. The control group received no treatment, whereas periodontitis was induced in both the PED and the MEL+PED groups, with the MEL+PED group being treated with systemic melatonin. For the periodontitis-induced groups, the rats' mandibular first molar teeth were ligatured (3-0 cotton) in a submarginal position for 4 weeks, and then the ligature was removed. After removal of the ligature, melatonin was administered only to the MEL+PED group (an ip dose of 10 mg/kg body wt for 15 days at 11:00 PM each day). In the histological examination, the MEL+PED group, which received the melatonin, showed reduced inflammatory cytokines (IL-1 beta, from 97.47 to 84.24 pg/ml; TNF-alpha, from 0.22530 to 0.22519 pg/ml), regulated oxidative stress parameters (MDA, from 41,458 to 30,708 nmol/g; GSH, from 18,166 to 25,858 nmol/mg), and less periodontal tissue destruction (CEJ-PL, lingual, from 244.54 to 140.57 mu m; buccal, from 235.6 to 158.93 mu m; and CEJ-BC, lingual, from 383.65 to 287.76 mu m; buccal, from 391.92 to 296.12 mu m). From these findings we conclude that, even when periodontitis was induced, melatonin reduced the oxidative damage in the rats' periodontal tissue by inhibiting the inflammatory effects and by restoring the antioxidants. (c) 2012 Elsevier Inc. All rights reserved.