Background & Objective: Lichen planus is a mucocutaneous disease which is relatively common and in 30-70% of patients, mucosal lesions can be seen and known as a precancerous lesion but its etiology is not completely understood. Desmogleins I and III are the main desmosomal transmembrane proteins. These proteins have been identified as the autoantigen of the autoimmune disease. The aim of this study was evaluation of serum autoantibodies against desmogleins Ι, ΙΙΙ in oral lichen planus. Methods: We attempted to determine the etiology of this disease with evaluation of these serum factors. Thirty-five patients with oral lichen planus and 35 healthy controls were recruited and tested for serum autoantibodies against desmogleins Ι, ΙΙΙ and indirect immunofluorescence also performed. Data were analyzed by statistical–analytical methods (Independent sample t-test) with using the SPSS.15 software. Results: Serum autoantibody against desmoglein Ι had no significant difference in the two groups (P=0.31) but significant increase in serum autoantibody to desmoglein ΙΙΙ was found in patients with oral lichen planus (P=0.00). Conclusion: It seems that autoantibody against desmoglein III has a significant role in the pathogenesis of oral lichen planus.