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OBJECTIVES The aim of the present study was to evaluate the antioxidant effect of systemically administered caffeic acid phenethyl ester (CAPE) in periodontitis. MATERIALS AND METHODS Forty rats were randomly divided into four groups: control, lipopolysaccharide-induced experimental periodontitis (LPS), CAPE 5: LPS+5 μmol/kg/day CAPE, and CAPE 10: LPS+10 μmol/kg/day CAPE. Following lipopolysaccharide-induced experimental periodontitis, CAPE was administered intraperitoneally for 28 days. Gingival and serumal total antioxidant status (TAS) and total oxidant status (TOS) were analyzed by enzyme-linked immunosorbent assay (ELISA). RESULTS Gingival tissue TAS was significantly higher with CAPE application compared with the LPS group and was highest in the CAPE 10 group (p<0.05). Gingival tissue TOS was highest in the LPS group, and both of the CAPE dosages decreased the gingival tissue TOS, with the highest decrease in the CAPE 10 group (p<0.05). The differences were not significant for serumal TAS or TOS levels (p>0.05). CONCLUSIONS The effect of CAPE on increased TAS and decreased TOS levels in inflamed gingival tissue indicates the antioxidant therapeutic potential of CAPE in periodontitis. CLINICAL RELEVANCE Within the limitations of this study, CAPE may be suggested as an effective host modulator agent for reducing oxidative stress in gingival tissue and might be considered as an adjunctive therapy in periodontitis.