We evaluated the effects of systemic infection by Herpes bovis virus 2 (HBV-2) on a murine experimental system. We provide evidence that such infection is lethal for the immunocompromised but not for the immunocompetent mouse in which a biphasic immune response is elicited. In particular, 1 day post-infection, we observed a rapid transient depression induced by the virus, as documented by a decrease in peripheral leukocyte counts, mitogenic spleen cell response and resistance to a secondary microbial challenge. Later, HBV-2 infection boosted cytokine secretion and enhanced antimicrobial and antitumoral activities by the splenic district. In conclusion, our experimental model discloses some immunological aspects underlying the complex host-virus interaction.