Macrophages restrict herpes simplex virus replication and can prevent the development of herpetic disease in mice. In an attempt to define the nature of this restriction, an analysis of virus-specified macromolecular syntheses in infected macrophages was undertaken. The significant results were the following: All cells were killed, but the infection was considered to be abortive since the level of infectious virus in macrophage cultures dropped steadily to a level beyond detection by 25 hr after infection. This restriction appeared to be specific for macrophages; the virus replicated efficiently in other mouse cells. DNA with a density characteristic for herpes simplex virus DNA was extracted from infected cultures, and the proportion of macrophages synthesizing DNA increased from less than 1% to greater than 50% by 6 hr after infection. Studies employing polyacrylamide gel electrophoresis indicated that the major viral-specific proteins were induced in macrophage cultures. In addition, all cells showing cytopathic changes characteristic of herpes virus infection also contained viral antigens which could be detected by fluorescent antibody techniques and, by 15 hr after infection, most contained nascent capsids lacking central dense cores. It is suggested that an error in DNA metabolism may be the primary cause of restriction.