The morbidity and mortality of neonatal herpes simplex virus infection remains unacceptably high despite antiviral therapy. A better understanding of factors that might contribute to this poor outcome is needed but has been hindered by a lack of a good animal model. The recently described guinea pig model of neonatal HSV-2 infection was used to explore the effect of age and route of inoculation on the outcome of infection. After intranasal inoculation the onset, extent, and severity of the primary disease, as well as the number of recurrent lesion days, varied inversely with age. The route of inoculation also affected the outcome. Newborn animals were inoculated either intradermally on the scalp or by the intranasal, oral or corneal route. Animals inoculated on the scalp had the best outcome with no deaths or evidence of neurologic disease while the intranasal route produced the most severe disease, 88% mortality. Neurologic disease was common after oral (41%) and corneal (56%) inoculation but resolved spontaneously whereas following intranasal (39%) inoculation all animals with neurologic disease died. Recurrent disease manifest by cutaneous lesions was observed in all survivors of each group but also differed by the route of inoculation. The guinea pig model of neonatal HSV-2 disease appears to mimic human disease. The studies presented here show that the outcome of infection is influenced by the age and route of inoculation.