Oral hairy leukoplakia occurs almost exclusively in human immunodeficiency virus (HIV)-infected patients and is predictive for the development of acquired immunodeficiency syndrome (AIDS). It presents as a white plaque with a rough surface, most commonly on the sides of the tongue. The eruption is frequently overlooked, and, because it is commonly mistaken for oral candidiasis, its true incidence is unknown. The leukoplakia is the result of permissive infection of epithelial cells by the Epstein-Barr virus. Antiviral therapy that inhibits Epstein-Barr virus replication can result in clinical improvement. Oral hairy leukoplakia provides a unique clinical model for investigations on the pathogenesis of Epstein-Barr virus infection.