Objective: The present study was carried out as a multicenter, randomized controlled, split-mouth clinical trial to evaluate the efficacy of locally delivered lycopene on periodontal health and gingival crevicular fluid (GCF) levels of 8-hydroxydeoxyguanosine (8-OHdG) in smokers and nonsmokers compared with periodontally healthy control subjects. Method and Materials: One hundred ten subjects including 50 smokers, 50 nonsmokers, and 10 controls participated in this study. Subjects in the smoker and nonsmoker groups had contralateral sites treated with lycopene gel and a placebo. Clinical parameters included recording site-specific measures of plaque, gingivitis, probing depth, and clinical attachment level. GCF 8-OHdG values were analyzed using a commercially available ELISA kit. Results: Compared with the placebo, lycopene-treated sites in smokers and nonsmokers showed significant reductions in probing depths and gain in the clinical attachment levels. However, there was no statistically significant difference in the clinical parameters when lycopene-treated sites in smokers and nonsmokers were compared, except for the reduction in the 8-OHdG levels. The 8-OHdG levels at 1 week and 3 months in sites treated with lycopene in the smoker and nonsmoker group were comparable with those in the periodontally healthy control group. Conclusion: The gel formulation was effective in increasing clinical attachment and reducing gingival inflammation, probing depth, and oxidative injury compared with the placebo in smoking and nonsmoking subjects. Keywords: antioxidants, lycopene, periodontitis, smoking