The interactions of Shope papilloma virus (SPV) with primate and rabbit cells in tissue culture have been investigated. The rabbit cell cultures were derived from normal epidermis, from SPV-infected epidermis, from SPV-induced papillomas, and from an SPV-associated carcinoma. None of these cell cultures, whether infected in vitro with SPV or derived from tissues infected in vivo, ever produced infectious SPV or even detectable viral antigens. Some other DNA viruses behaved differently in cells which had been in previous contact with SPV either in vitro or in vivo. Adenovirus type 5 multiplies better in human cells infected 24 h previously with SPV than in the untreated controls. The production of infectious virions of either herpes simplex virus or Shope fibroma virus is reduced in cells derived from SPV-induced papillomas or carcinoma, due, apparently, to a defect in viral maturation. Of the rabbit cells, only those derived from in vivo infected tissue, or those previously infected in vitro with SPV, could be transformed by SV40. The rabbit cell lines derived from papillomas or carcinoma differed from their counterparts derived either from normal epidermis or from tissue infected 24 hrs before biopsy, in their karyotype, and in their ability to grow in soft agar. Similar karyotypic alterations were induced in cells derived from healthy epidermis by infection in vitro with SPV.