Ten HIV-infected patients who had bilateral hairy leukoplakia on the tongue were treated with topical podophyllum resin 25% solution. Only one side of the bilateral lesion was treated and the other side served as the control and was not treated. The lesions on both the treatment and control sides were evaluated at day 2, 7, and 30 by an investigator who had not been involved in the initial treatment and had no knowledge of which side had been treated. Therefore the treatment side is compared with the control side in a single-subject design, single-blind control setting. The lesions were judged by the degree of resolution and assigned a number of 0 to 4 with 4 indicating the highest degree of resolution and 0 indicating no resolution or worsening of the condition. The results were analyzed by Student's t test. Significant resolution of hairy leukoplakia was noted on the treatment side compared with the control side at the 2-, 7-, and 30-day levels; the 2-day results were the most significant. Furthermore, the patients reported minimal side effects, which included burning sensation, bad or altered taste, and pain, that were of mild intensity and short duration. The side effects were reported to occur immediately after the topical application. Patient tolerance and acceptance were found to be very favorable. No systemic side effect was reported. We conclude that single topical application of podophyllum resin 25% solution is efficacious in producing significant short-term resolution of HIV-related oral hairy leukoplakia. We also conclude that it is a safe topical regimen with minimal side effects.