Herpes Simplex Virus 1 (HSV1) is capable of inducing two forms of infection in individuals, and the establishment of which type of infection occurs is linked to the transcriptional activation of viral alpha genes. One of the HSV1 alpha genes, ICP22, is known to have multiple functions during virus replication, but its distinct roles are still unclear. This study showed that ICP22 functions as a general repressor for certain viral and cellular promoters, and this transcriptional repression by ICP22 is independent of the specific upstream promoter element, as shown using the CAT enzyme assay system. Further work also found that VP16 interfered with ICP22 mediated transcriptional repression of the viral alpha4 gene, through interactions with specific elements upstream of the alpha4 gene promoter. These findings support the possibility that ICP22 and VP16 control transcription of HSV1alpha genes in a common pathway for the establishment of either viral lytic or latent infections.