Background: Pemphigus vulgaris is a rare autoimmune disorder characterized by cutaneous and mucosal blistering. Surprisingly, the management of oral lesions has been detailed only infrequently. As current topical therapies for oral lesions are of limited efficacy, application of calcineurin inhibitors is considered to be a potential option. The aim of this essay was to investigate the efficacy of tacrolimus 0.1% ointment (Protopic®) versus triamcinolone acetonide 0.1% paste (Volon-A®) in the treatment of oral pemphigus vulgaris. Method: Fifteen patients were involved in a prospective randomized trial with a split- mouth design. After two weeks of administering study drugs, oral lesions were monitored and quantified pain and mucosal surface involvement scores were obtained. Result: Within 14 days, the degree of involvement and pain scores significantly reduced in both tacrolimus-treated and triamcinolone-treated sites, but there was no significant difference between them. No severe adverse events were observed. Conclusion: This study showed that tacrolimus could be as effective as triamcinolone acetonide in the topical treatment of oral pemphigus vulgaris.