Herpes simplex virus type 1 (HSV-1) is transcriptionally active during latent infection in human peripheral sensory ganglia. Viral gene expression includes the latency-associated transcripts (LATs) which have been linked to the ability of the virus to resume replication and reactivate. However, the molecular basis of reactivation and the mechanisms of action of these transcripts are unknown. In order to study these parameters, an in vivo reactivation model is needed. We investigated use of the mouse as the experimental animal, modifying the route of infection, the viral strain and the reactivation protocol. Following administration of human immunoglobulin 1 day prior to corneal infection, no infectious virus was detected in trigeminal ganglia (TG). However, latency was established in all infected animals as indicated by explant reactivation of TG, and in vivo reactivation was achieved in 30 to 40% of them. DNA quantification revealed that TG of immunized mice contained more HSV-1 DNA than did those of non-immunized mice. By in situ hybridization twice as many neuronal cells in TG of immunized mice were positive for LATs, compared with infected but non-immunized, mice. These findings suggest that suppression of primary infection facilitates reactivation by increasing HSV-1 copy number in latently infected nervous tissue.