The aim of the present study is to verify the efficacy of isotretinoin in oral lichen planus (OLP). In a double-blind study, ten patients with biopsy-proven OLP were treated for 4 months with 0.1% isotretinoin gel and another ten patients with placebo. At the end of the first period of observation, the patients who had been given the placebo were given isotretinoin for a further 4 months. A complete response was defined as the disappearance of the lesions as assessed by inspection, whereas a partial response was defined as a 50% or more reduction in the size of the lesions. All patients treated with isotretinoin showed a significant improvement of the oral lesions, whereas in the patients who were given the placebo, the size of the lesions remained the same. The patients who were given isotretinoin after the placebo showed a reduction in lesions. In total, there were ten complete and ten partial responses. Lesions were analysed histologically and immunohistochemically with antibodies against bcl-2 and Ki-67. Ki-67 and bcl-2 have statistical significant increased values from before to after treatment, whereas apoptotic bodies decreased one. All these facts could have contributed to the partial or complete regression of OLP lesions. The increase in Ki-67 positive cells show that the epithelium requires for enhanced proliferation and healing. The present results revealed a disturbed cell death programme in OLP that could underline an abnormal epithelial differentiation. The results of this pilot study show that the topical use of isotretinoin is effective in treating OLP.