Background: Oral leukoplakia is a condition commonly associated with tobacco use. The literature also has documentation pertaining to likely cancerous transformation of leukoplakia. It is always a challenge to discover a therapeutic modality to prevent this transformation. Imiquimod is an immune response modifier possessing antiviral and anti-tumor activity which is being explored as an off label use in many cancerous conditions. Aim: To show any regression in oral leukoplakia and to test its safety and tolerability. Setting and Design: This is a randomized, open-label, single-centered clinical pilot study carried out with Imiquimod. Material and Methods: Two groups OPD of dental college with topical 5% Imiquimod and Topical Vitamin A (50,000 IU) were compared for their efficacy in the management of oral leukoplakia, pre- and post-treatment clinically and regression of oral dysplasia was observed histopathologically. Unit of improvement was noted for assessing the effectiveness of treatment. Statistical Analysis: Quantitative data were analyzed by Wilcoxon signed test. Results: Topical 5% Imiquimod application resulted in good clinical response +1, +2 unit of improvement with more regression of lesion noted in non-homogeneous leukoplakia and areas with less salivary contamination. Topical Imiquimod 5% is the best alternative to conservative management of moderate to severe dysplasia cases where we can offer more to the patient than just observation, and it is also better than a surgical option where surgery leads to more morbidity, in recurrent cases.