Nuclear factor jB (NF-jB) is associated with the transcriptional activation of genes encoding chemokines, adhesion molecules, cytokines, and anti-apoptotic proteins, which are key components in immune responses and viral infection. Many viruses modulate NF-jB through numerous viral gene products to allow productive infections and immune escape. Here we report that herpes simplex virus-1 infected cell protein 27 (HSV-1 ICP27), an immediate early protein of HSV-1, represses NF-jB activity through binding to inhibitor of jB (IjBa), blocking phosphorylation and ubiquitination of IjBa, and stabilizing IjBa. These data may explain how NF-jB activity is regulated by ICP27 to escape immune responses during the very early period of HSV-1 infection.