Vaccinia virus complement control protein (VCP) is encoded by vaccinia virus, with its homolog encoded by other pathogenic poxviruses including variola virus. Since rodents are the primary reservoir hosts of cowpox virus (CPV) and since CPV encodes a highly conserved functional homolog of VCP, termed here the inflammation modulatory protein (IMP), the effects of injection of CPV into the footpads of mice was determined in order to study the precise in vivo effects of IMP. Macroscopic examination of the site of injection with a recombinant virus lacking IMP (CPV-IMP) showed greater tissue damage, with more hemorrhage and induration, than sites injected with the wild-type cowpox virus. In addition, the measurement of the specific swelling response carried out for several weeks revealed significantly greater swelling in mice injected with CPV-IMP. Thus, IMP modulates the complement-activated inflammatory response in vivo. Furthermore, the diminished destruction of host tissue observed in the presence of IMP indicates symbiosis in which the virus ensures the preservation of surrounding host tissue, possibly to support the growth of its progeny.