A variety of biological response modifiers (BRMs) have provided antiviral protection to immunocompetent mice, and this prompted us to determine their efficacy against murine cytomegalovirus (MCMV) infection in immunocompromised mice-including the profoundly immunocompromised SCID mice and C57Bl/6 and B6D2F1 aged mice. SCID mice showed a marked decrease (> 20-fold) in resistance to MCMV, while there was a slight decrease (3-fold) in aged mice. In BRM antiviral protection studies, SCID mice were almost completely protected against MCMV infection by the pleiotropic immunomodulators, MVE-2 and pICLC, but much less by the more selective CSF-1. pICLC-induced IFN and NK cell cytotoxicity were maintained in SCID mice, suggesting that pleiotropic immunomodulatory effects may be required for antiviral protection in such a profoundly immunocompromised model. pICLC also effectively protected aged mice against lethal MCMV infection and effectively induced IFN. These results emphasize the potential for BRM treatment in immunocompromised hosts.