Background and objective: Periodontitis is a common, chronic inflammatory disease characterized by formation of a periodontal pocket and can lead to tooth loss. Several studies found increase in serum C- reactive protein (CRP) and malondialdehyde (MDA) in patients with periodontitis, while alkaline phosphatase (ALP) showed a decrease. The present study was aimed to investigate and evaluate the effects of eicosapentaenoic acid (EPA) on ligature induced periodontitis in rats through the biochemical analysis for rat’s serum level of CRP, ALP and MDA. \nMethods: Periodontitis was induced for the studied animals by ligation around the upper central incisor. Twenty five animals were used as a control and gavaged by water only, and one hundred animals with the induced periodontitis were divided into four equal groups according to the treatment used which was started at time of ligation removal: Water (P/W), scaling/root planing (P/SRP), 60mg/kg EPA(P/EPA), and scaling/root planing together with EPA(P/SRP+EPA). Blood was taken by cardiac puncture, after three hours, 24 hours, three days, one week and two weeks for biochemical analysis.\nResults: The P/SRP+EPA treatment group showed significant decrease (p<0.05) in serum CRP, significant increase in serum ALP, significant decrease in serum MDA after one week, three days, and three hours respectively in comparison with the P/W treatment group.\nConclusion: The treatment by SRP with 60mg/kg EPA is better than each one alone and can be used for treatment of periodontitis.