We have examined the macrophage and microglial cell response in mouse brains during the course of acute herpes simplex encephalitis produced by intranasal inoculation of virus. Macrophage infiltration and a microglial cell reaction were detected from 24 h after initial detection of HSV-1 antigen in brain. Macrophage infiltration was confined to focal areas of infection but the microglial cell reaction occurred in a more widespread distribution. Following disappearance of viral antigen, with resolution of the acute infection, macrophage infiltration and a focal microglial cell reaction remained for several weeks, providing a marker of sites of previous infection.