Latent human papillomavirus infection, a very common event, is most likely the source of primary and recurrent papillomas of the respiratory and genital tracts and might also be the source of neoplastic lesions of the female genital tract and the penis. We have developed a simple model for papillomavirus latency using cottontail rabbit papillomavirus. Skin of domestic rabbits was minimally scarified and inoculated with dilutions of a crude virus suspension ranging from 200 ng to 20 pg viral DNA per inoculated site. Dilution of virus to less than 10 ng/site resulted in delayed and reduced efficiency of inducing warts. After follow-up of 1 to 6 months, sites immediately adjacent to papillomas and inoculated sites where papillomas did not form were biopsied and analyzed by Southern blot and polymerase chain reaction. Inoculated tissues that were clinically and histologically normal contained viral DNA at low levels, detectable by polymerase chain reaction. Ability of the latent virus to induce warts was confirmed by activation with mild skin irritation causing wart formation. This simple model system for latent papillomavirus can be used to study mechanisms of viral activation, therapies to prevent activation, and therapies to eliminate latent virus and thus cure the infection.