The efficacy of desciclovir, an analog of acyclovir, in eliminating lesions of oral hairy leukoplakia (HL) and suppressing Epstein-Barr virus (EBV) infection was evaluated in a double-blind, placebo-controlled study of 14 patients. Patients were randomized to receive either the active drug, 250 mg three times a day for 14 days, or placebo. In all eight patients receiving desciclovir, lesions of HL were either completely resolved or significantly reduced during the treatment period, whereas lesions in patients receiving placebo showed no change. The histological features of HL were significantly diminished in patients on desciclovir, and cytochemical, in situ hybridization, and ultrastructural studies showed that EBV infection was eliminated or dramatically reduced in the desciclovir group only. Four patients on desciclovir reported side effects, but none required withdrawal from the study. The reappearance of HL in all eight subjects on desciclovir within 1–4 months after therapy was discontinued suggests the need for additional study.