Cytomegalovirus (CMV) is the most common cause of congenital infection in the developed world and can lead to a life-threatening disease. We therefore developed an animal model to evaluate candidate anti-CMV drugs and to further define the pathogenesis of CMV infections. Newborn guinea pigs were infected by intraperitoneal administration of 10(6) pfu of a virulent salivary gland (SG) passaged guinea pig CMV (gpCMV) within 48 h of birth. Inoculation of animals produced 50% overall mortality. A lack of weight gain was also a hallmark of infection. By day 14 after inoculation the weight of gpCMV-infected animals was significantly less than controls (152.9+/-45 g versus 254.7+/-38.5 g, P<0.0001). The most consistent isolation and highest titers of virus were found in the liver and spleen early while lung titers were maximal at day 10. A quantitative competitive PCR (qcPCR) assay confirmed the presence of a high CMV viral load in infected organs. Antiviral treatment with cyclic HPMPC (cHPMPC) for 7 days significantly reduced mortality (1/20 versus 14/20, P<0.001) and viral replication but did not improve weight gain. This model should be useful for further evaluations of the pathogenesis of CMV infections and for evaluation of antiviral drugs and vaccines.