The aim of the current study was to evaluate, in an open trial, the clinical efficacy of topical calcipotriol compared with tretinoin in the therapy of hyperkeratotic oral lesions (leukoplakia). The study group consisted of 40 patients with histologically proven oral leukoplakias, 20 treated with calcipotriol, the other 20 with tretinoin. The treatment was for 5 weeks and follow-up at 4 months, with clinical assessments at 2, 4 and 5 weeks and regular laboratory assessments. The results showed a significant reduction in lesions (80%), in both calcipotriol and tretinoin groups, with no documented topical or systemic adverse reactions, results maintained at 4 months. Tretinoin however, potentially can induce erythema, angular cheilitis and xerostomia. The study suggests that topical calcipotriol is as effective in the therapy of oral leukoplakia as is topical tretinoin.