Aims and Objectives: A randomized controlled study was carried out to evaluate the efficacy of lycopene in combination with vitamin E and selenium in the treatment of leukoplakia in patients visiting dental college Jharkhand. Materials and Methods: Forty patients of leukoplakia were randomly categorized (irrespective of size and severity of the lesions) in two groups: Group A and B. Group A consisting of 20 patients were administered combination of lycopene (3 mg), vitamin E (200 I.U.) and selenium (100 mcg) twice daily and group B consisting of 20 patients were given placebo capsules once daily for a period of 4 months. Post-treatment follow-up period was 3-4 months. The product used in the study was LYC-O-MATO soft gels, manufactured by Mano pharmaceuticals, Chennai, India. The treatment outcome was evaluated both clinically and histologically and the results were statistically evaluated using Student’s unpaired ‘t’ test. Results: The results showed that the patients receiving lycopene in combination with vitamin E and selenium have statistically significant improvements both clinically and histologically as compared to those receiving placebo and with no side effects. Conclusion: The study results proved that the efficacy and safety of lycopene along with selenium and vitamin E in the management of oral leukoplakia.