ObjectivesWe aimed to assess the effectiveness of the use of topical imiquimod for the management of oral leukoplakia (OL).MethodsThis was a retrospective study. Medical chart reviews were conducted to identify patients with biopsy‐proven OL treated with topical 5% imiquimod. Data included OL characteristics, histopathological diagnosis, treatment outcome, and adverse events (AEs). Treatment response was assessed by measuring the percentage reduction in the size of OL lesions.Results33 patients (51.5% females; median age: 65 years) with 38 lesions were included. OLs were either localized (23.7%) or multifocal lesions (76.3%), with the majority on the gingiva (86.8%). Pretreatment histopathological diagnoses were dysplasia in 84.2% and nonreactive hyperkeratosis in 15.8%. Most regimens consisted of 60‐minute applications, 5‐days‐a‐week, for 6 weeks. At the end of treatment, 81.6% of 38 lesions showed a reduction in size with 68.4% exhibiting ≥50% reduction in size, and 42.1% exhibiting complete resolution. Application site reactions were the most common with pain/soreness/sensitivity occurring in 86.8%. Fatigue was the most frequently reported systemic AE (28.9%).ConclusionTwo‐thirds of OL lesions had ≥50% reduction in size. Most AEs were temporary and resolved upon treatment discontinuation. Prospective studies are needed to further assess Imiquimod's effectiveness in OL management.