PrPc is a glycophosphatidylinositol-linked cell-surface protein expressed principally by neural tissue. The normal function of this protein is unestablished, although a role in either transmembrane signaling, cell-cell adhesion, or copper metabolism has been proposed. In this study we have investigated the effect of the neurotropic virus herpes simplex virus type 1 (HSV-1) in strains of mice which express different levels of PrPc. Viral gene expression under the control of the HSV-1 early promoter IE110, detected either by in situ hybridization for RNA transcripts or by β-galactosidase (β-Gal) activity from an inserted lacZ gene, showed that the magnitude of HSV replication was retarded in PrP−/− mice. This was reflected in the lower level of acute viral titers in tissues from these virus-inoculated mice. However, HSV-inoculated PrP−/− mice contained higher levels of latent virus in both peripheral and central nervous tissue than those seen in mice which express PrPc. Our observations show that lack of PrPc expression favors the establishment of HSV latency whereas HSV replication proceeds more efficiently in neuronal tissue that expresses this protein. The data further suggest that PrPc may be involved in a metabolic pathway that culminates in apoptosis of neurons that have been infected by neurotropic viruses.