Macrophages are known to play a critical role in host resistance to herpes simplex virus (HSV). In this study, we investigate the interaction between various HSV strains with different virulence and a murine macrophage cell line, RAW264. Highly attenuated strains replicated poorly in RAW264 cells and were cleared from the cultures. For the eleven viruses tested, there was good correlation between intraperitoneal pathogenicity for adult mice and replication in RAW264 cells. It was also shown that interferon alpha/beta was involved in restricted replication of some strains.