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Molluscum contagiosum virus (MCV) is a common pathogen causing a troublesome skin condition in many immunocompetent individuals and a widespread, disfiguring affliction in many patients with AIDS. We have successfully infected human foreskin fragments with a patient-derived isolate of MCV. This was demonstrated by exposing the foreskin pieces to a patient lesion extract and implanting the tissue under the renal capsule of athymic mice. Light and electron microscopic examination of infected implants showed the presence of cytoplasmic inclusions containing typical poxvirus particles within 2-3 weeks of implantation. Replication of MCV was established by demonstrating that viable virus was required to produce the cytopathologic effects, and viral DNA replication was demonstrated by incorporation of bromodeoxyuridine into cytoplasmic inclusions. Four additional patient extracts (representing both described MCV types) were also used to successfully infect foreskin implants. A limited number of attempts to pass virus from one infected implant to another were not successful. This system is the most rapid and reproducible for growing MCV that has been reported to date.