Four human immunodeficiency virus-positive homosexual men with 2- to 4.5-year histories of recurrent oral warts that had failed to respond to conventional surgical and other treatment modalities were offered treatment with interferon-alpha. All had multiple or large oral warts, 3 had skin warts, 2 had a history of anal warts, and 1 had penile lesions. All 4 patients were treated with a combination of intralesional and subcutaneous interferon-alpha. Adverse side effects were dose-related, mild, and transient; they included flulike symptoms (3 patients), hair loss and tachycardia (1 patient), and transient changes in the white blood cell count. All patients responded to therapy and remained free of disease up to 42 months. Intralesional injection with interferon-alpha appears to provide excellent clinical control for recurrent, multiple, and extensive oral warts in the human immunodeficiency virus-positive population, and is a useful adjunct to initial surgical removal of oral warts.