Lichen planus is a common chronic inflammatory mucocutaneous disease, affecting 0.1% to 4% of the general population. There is no published randomized active control clinical trial on pimecrolimus for the treatment of oral lichen planus (OLP). The purpose of this study was to compare the efficacy and safety of pimecrolimus 1% cream with triamcinolone acetonide 0.1% paste in treating OLP. In this investigator-blinded parallel-group randomized clinical trial, 40 patients were randomly assigned in two equal groups to receive either pimecrolimus 1% cream or triamcinolone acetonide 0.1% paste 4 times daily for a total of 2 months and followed up for another 2 months. The patients were assessed for painful symptoms measured by visual analog scale, the Oral Health Impact Profile score, and objective clinical score. Nonparametric tests were used to assess the main outcomes. Intention-to-treat analysis was used. Eighteen patients in pimecrolimus group and 17 patients in triamcinolone group finished the 4-month trial course. Both pimecrolimus and triamcinolone groups showed significant improvement in all measured efficacy end points throughout the visits. There was no significant difference between changes from baseline median values of pimecrolimus and triamcinolone groups after treatment termination in terms of visual analog scale score (-9.8 +/- 11.3 vs -8.4 +/- 18.3, P = .70), Oral Health Impact Profile score (-1.5 +/- 2.6 vs -1.6 +/- 2.1, P = .38), and clinical score (-0.7 +/- 0.6 vs -0.8 +/- 0.7, P = .86), respectively. Two patients in pimecrolimus group experienced prominent but transient burning sensation whereas none of the patients in triamcinolone group had any prominent adverse event (P = .24). Blood levels in pimecrolimus group were not measured and carcinogenicity of pimecrolimus, especially in its long-term use for OLP, is yet to be determined. This study showed that patients with OLP may benefit from both topical pimecrolimus and triamcinolone acetonide therapy with minimal side effects. Further studies should be conducted to assess the maintenance effects and long-term safety of both drugs (Cochrane skin group identifier: CSG TrialNo. 22).