Molluscum contagiosum virus (MCV) infects preadolescent children and sexually active adults, frequently causing a disfiguring cutaneous disease in immunosuppressed HIV-infected individuals. The development of an efficacious treatment regime has been hampered by the failure to replicate the virus in the laboratory. Here we report the first demonstration of MCV replication in an experimental system. In human foreskin grafts to athymic mice, MCV induced morphological changes which were indistinguishable from patient biopsies and included the development and migration of molluscum bodies containing mature virions to the epidermal surface.