ABSTRACT Severe adenovirus infections in transplant recipients undergoing immunosuppressive therapy are of increasing concern. Controversy exists on the contribution of antiviral therapy and the host immune response to recovery from these infections. Here, we established a systemic mouse adenovirus type 1 (MAV-1) infection in cyclophosphamide (CyP)-treated BALB/c mice. CyP was administered at 100 mg per kg of body weight every other day for 2, 3, or 4 weeks, thereby inducing general but reversible leukopenia, with a major suppression of the B-cell numbers and functionality that was more pronounced than that seen with T cells. The outcome of MAV-1 infection was dependent on the duration of CyP therapy, as the mice with the most severe immunosuppression were the most vulnerable to MAV-1-induced hemorrhagic enteritis and mortality. The protective effect of concomitant antiviral therapy with cidofovir depended on the level of immunosuppression. The combination of cidofovir treatment with the withdrawal of immunosuppression was the most successful regimen for increasing survival rates. Survival was clearly correlated with the clearance of virus and increased titers of MAV-1-specific antibodies in sera. In addition, the passive transfer of MAV-1-specific immunoglobulin G into MAV-1-infected SCID BALB/c mice caused a marked delay in mortality, the extent of the delay being dependent on the titer of MAV-1-specific antibodies. Based on the critical role of the humoral immune response in the early defense against disseminated adenovirus infection, the concomitant use of adenovirus-specific immunoglobulins and antiviral therapy should be considered for transplant patients at risk for severe adenovirus infections.