Recent studies have explored the chromatin structures associated with the herpes simplex virus type 1 (HSV-1) genome during latency, particularly with regard to specific histone tail modifications such as acetylation and dimethylation. The objective of our present study was to develop a rapid systemic method of in vivo HSV-1 reactivation to further explore the changes that occur in the chromatin structures associated with HSV-1 at early time points after the initiation of HSV reactivation. We present a uniform, rapid, and reliable method of in vivo HSV-1 reactivation in mice that yields high reactivation frequencies (75 to 100%) by using sodium butyrate, a histone deacetylase inhibitor, and demonstrate that the reactivating virus can be detected at the original site of infection.