Animal models of human cytomegalovirus (CMV) infections have not been available to study pathogenesis or to evaluate antiviral drugs. Severe combined immunodeficient mice implanted with human fetal tissues (SCID-hu) were found to support CMV replication and may provide a model for this species-specific virus. When conjoint implants of human fetal thymus and liver were inoculated with a low-passage-number isolate of CMV, strain Toledo, consistent high-level viral replication was detected 5, 12, 15, 28, and 35 days after inoculation and virus replication continued for up to 9 months. Other human tissue implants, including lung and colon, were also found to support viral growth but with greater variability in levels and for a shorter duration. As expected, the species specificity of human CMV was preserved in this model such that virus was detected in the human conjoint thymus/liver implant but not in surrounding mouse tissues. The majority of virus-infected cells were localized in the thymic medulla rather than cortical region of the implant and immunofluorescence analysis identified epithelial cells rather than any hematopoietic cell population as the principal hosts for viral replication. Finally, treatment of infected animals with ganciclovir reduced viral replication, thereby demonstrating the value of this system for evaluating antiviral therapies. This animal model opens the way for a range of investigations not previously possible with human CMV.