BACKGROUND Lichen planus disease is a chronic inflammatory disorder of mucosal and cutaneous tissues with yet unclear etiology and pathogenesis. Cytokines play an important role in the initiation, maintenance of inflammatory and intercellular crosstalk. OBJECTIVE We assessed serum levels of IL-22 in patients with oral and cutaneous lichen planus and made comparison with healthy individuals. METHODS In this case-control study, peripheral blood samples of 40 patients with lichen planus disease, included two groups of oral lichen planus (n=20) and cutaneous lichen planus (n=20) were compared with 32 healthy individuals in this case-control study. Serum samples were prepared from patients with lichen planus and IL-22 concentration was measured in each serum sample by using a commercial ELISA Kit. The obtained data were then analyzed using the Kruskal-Wallis (one-way ANOVA) test. RESULTS The IL-22 serum levels were significantly higher in patients with oral lichen planus compared to the healthy control group (p< 0.001). No statistically significant differences were observed in serum levels of IL-22 in cutaneous lichen planus patients compared to the controls (p= 0.183). CONCLUSIONS Increased IL-22 serum levels in patients with oral lichen planus may play an important role in the pathogenesis of oral lichen planus. The administration of the recombinant or antagonist of IL-22 could be a new therapeutic opportunity in the treatment of oral lichen planus.