Cytokine profiles during cowpox and vaccinia (WR strain) virus infections were characterized in intranasal (i.n.) and intraperitoneal (i.p.) models in BALB/c mice. The time-course of induction and effects of cidofovir treatment on interferon (IFN)-γ, IFN-γ inducible protein (IP)-10, interleukin (IL)-6, and monocyte chemoattractant protein (MCP)-1 were determined. The four mouse infection models have distinct patterns of cytokine induction. Cowpox virus i.p. and vaccinia virus i.n. infections showed increased induction throughout the time studied. Cowpox virus i.n. infection resulted in delayed induction of IFN-γ and IP-10. Cytokine levels were fairly constant during vaccinia virus i.p. infections. Cidofovir treatment (100 mg/kg/day i.p. for 2 days) significantly suppressed certain cytokine (IFN- γ, IL-6, IL-10, IL-11, IP-10, LIF, MCP-1, MCP-3, MCP-5, MIP-1γ, and TIMP-1) levels to near normal relative to uninfected animals, as well as prevented mortality and reduced virus titers significantly. Characterization of cytokine responses has implications for understanding the immune responses and pathogeneses of viral infections in these mouse models.