A high proportion of depilated newborn or euthymic congenitally hairless adult guinea pigs develop an erythematous papular exanthem during infection with varicella-zoster virus (VZV) previously cultivated in guinea pig cell culture. Virus has been demonstrated in tissues during varicella using polymerase chain reaction amplification and nucleic acid hybridization methods. The frequency of exanthem expression can be reduced by the prophylactic administration of VZV convalescent-phase guinea pig serum. This model should prove useful for further study of VZV pathogenesis as well as for testing putative antiviral compounds.