Background & Aim: Smoking represents a very significant epigenetic risk factor for not only the development of periodontitis, but also influences its severity and reduces treatment response. An anti-oxidant, resveratrol (trihydroxystilbene) blocks neutrophil recruitment and oxidative bursts, lessen oral inflammatory load, thereby reducing clinical manifestations of periodontitis. Material and Methods: Fifteen smoker male patients with an age range of 31–50 years and suffering from moderate to severe periodontitis (stage III periodontitis, clinical attachment loss ≥5, mostly horizontal bone loss) with clear medical history were included in the study. Using a split mouth design, sites were randomly allocated using a coin-flip method into two groups; Control group (Group I) received locally delivered resveratrol gel in all sites with probing depth ≥ 5 mm after SRP. Test sites (Group II) received only subgingival scaling and root planning (SRP) + placebo gel. Both gels application were repeated at 7, 14 and 21 days. Gingival crevicular fluid samples for evaluation of superoxide dismutase (SOD) enzyme were collected and clinical parameters [plaque index (PI), probing pocket depth (PPD), clinical attachment level (CAL), bleeding index (BI)] were recorded at baseline, 3 and 6 months evaluation periods. Results: Baseline values showed no significant differences between the two groups for all the studied parameters. After applying student’s Paired t-test, results showed a statistically significant decrease in PI and BI from baseline to 6 months in both groups as compared to their baseline value P<0.05. While PPD and CAL group I (control group) showed statistical significant decrease up to 3 months only followed by increase in their mean scores reaching the baseline value while in group II there are significant decrease up to 3 months followed by slight increase at 6 months but still statistically significant reduction as compared to the baseline values P<0.05. Regarding SOD levels were significantly improved in test sites when compared with control sites. Conclusion: Smokers patients treated with resveratrol demonstrated earlier responses to treatment compared to those on SRP only study demonstrated the potential benefits of resveratrol, as an adjunctive treatment to SRP. Further research should be conducted with larger cohorts to examine the benefits of resveratrol in patients with periodontal diseases, particularly those with co-morbidities or those who don’t like surgery.