The administration of interferons can be resorted to, either on its own or in combination with physical destruction methods, when the extent of genital HPV is widespread. Extensive genital HPV involvement is often seen in HIV-positive patients as a consequence of their immunodeficiency. The extension of these lesions may invalidate treatment by physical destruction, while an underlying immunodeficiency renders interferon therapy less efficacious. We studied HIV-positive and HIV-negative patients with a similar HPV involvement of their genital tract and compared the effectiveness of systemically administered alpha 2b and beta interferons in clearing HPV. Our results confirm that interferon therapy will cure most patients with extensive genital HPV when they are HIV-negative. HIV-positive patients with CD4 counts over 400 lymphocytes/mm3 may expect a similar cure rate, but this halves when this critical threshold is crossed. In these severely immunodeficient patients repeated courses of interferon therapy alone or in combination with physical destruction methods may be required to cure HPV infection.