Intranasal inoculation of newborn guinea pigs with herpes simplex virus (HSV) resulted in local skin-eye-mouth (SEM), central nervous system (CNS), and disseminated infections with high but not universal mortality. Cutaneous HSV inoculation produced self-limited SEM infection without evidence of CNS or disseminated disease. HSV infection of the upper respiratory tract of the newborn guinea pig resulted in early spread to the CNS and frequent viral dissemination. The outcome of infection was favorably affected by treatment with acyclovir. Spontaneous cutaneous recurrences occurred in most survivors. The newborn guinea pig should provide a useful model to explore both the pathophysiology and control of neonatal HSV infection.