The Florida manatee (Trichechus manatus latirostris) is one of the most endangered marine mammals in American coastal waters. Naturally resistant to infectious disease, the manatee immune system appears highly developed to protect it against the harsh marine environment and the effects of human-related injury. In 1997, seven captive Florida manatees developed multiple, cutaneous, pedunculated papillomas over a period of 6 months. Approximately 3 years later, four of the seven manatees developed multiple, cutaneous, sessile papillomas topically and clinically distinct from the initial lesions, some of which are still present. Histologic, ultrastructural, and immunohistochemical features indicated that the two distinct phenotypic lesions were caused by papillomaviruses (PVs). Preliminary immunologic data correlated with daily clinical observations suggested that the manatees were immunologically suppressed and that the papillomas were caused by activation of latent PV infections and reinoculation from active infections. The emergence of PV-induced papillomas in captive manatees, the possibility of activation of latent infection or transmission of active infection to free-ranging manatees, and the underlying cause of immune suppression predisposing manatees to develop viral papillomatosis are serious concerns for the future management of this highly endangered species.