Objective: This study aimed to investigate the anti-inflammatory effect of two different dosages of caffeic acid phenethyl ester (CAPE) on lipopolysaccharide-induced experimental periodontitis (EP). Material and Methods: Forty Sprague Dawley rats were randomly divided into four groups: control, EP, EP treated with 5 μmol/kg/day of CAPE (EP+CAPE 5), and EP treated with 10 μmol/kg/day of CAPE (EP+CAPE 10). Followed by the EP, CAPE was administered intraperitoneally to the EP+CAPE groups for 28 days. Samples were investigated biochemically using an enzyme-linked immunosorbent assay kit and alveolar bone loss was measured morphometrically. Results: In both of the CAPE groups, the levels of interleukin-1 beta and tumor necrosis factor alpha (TNF-α) in the gingiva were significantly lower than those in the EP group (p<0.001). The decrease in tissue levels of TNF-α was greater in the EP+CAPE 10 group than in the EP+CAPE 5 group in a dose-dependent manner. Serum analysis of the cytokines showed no significant difference between the groups. Conclusion: Within the limits of this study, CAPE showed an anti-inflammatory effect and is claimed to be a novel agent in improving the results of periodontal therapy. CAPE may be valuable as an alternative host modulating agent for the treatment of periodontal disease.