Aim: This study was designed to evaluate the clinical and biochemical effects of combination of hyaluronic acid and metronidazole as an adjunctive treatment of periodontitis. Subjects and methods: Forty patients with stage I to stage II, grade A periodontitis were selected from the out-patient clinic, Oral Medicine and Periodontology Department, Faculty of Dental Medicine, Al-Azhar University, Assiut Branch. They were divided into four equal groups. Group I received conventional periodontal therapy alone, group II received conventional periodontal therapy with intra pocket application of hyaluronic acid gel (GENGIGEL) 0.2%, group III received conventional periodontal therapy with intra pocket application of metronidazole (25%) and group IV received conventional periodontal therapy with intra pocket application of combination of hyaluronic acid (0.2%) and metronidazole (25%). All patients were evaluated clinically at baseline, 3 and 6 months and biochemical evaluation was done at baseline,1 and 3 months to evaluate the IL-1β level in GCF. Results: All groups showed statistically significant differences at the different intervals in all clinical parameters (PI, GI, PD, CAL) and IL-1β level in GCF. Inter-groups comparison with respect to clinical and biochemical changes showed that Combination gel was the best. Conclusion: The combination of hyaluronic acid and metronidazole achieve superior effects as adjunctive therapy in improving the clinical and biochemical parameters in the treatment of periodontitis.