p53 is a multifunctional host cellular protein in the cellular response to a broad range of stress because of its ability to regulate various cellular pathways. Recently, we reported that p53 plays an important role in the replication of herpes simplex virus type 1 (HSV-1) in a cultured cell line (Maruzuru et al., J. Virol., 2013). However, the involvement of p53 in viral pathogenesis remains unclear. To investigate the effect of p53 knock-out on global viral and host cellular gene expression in the brains of infected mice, we performed whole-transcriptome shotgun sequencing analysis of the brains from infected p53+/+ and p53-/- mice following intracranial infection.