Therapy of cytomegalovirus (CMV) infection in recipients of hematopoietic stem cell transplantation (HSCT) by immune serum transfer did not fulfill the high clinical expectations, although immune sera or immunoglobulin-enriched preparations pooled from many CMV-immune donors are likely to contain virus neutralizing antibodies covering a broad range of virus variants. Likewise, the highest risk of CMV disease in HSCT recipients results from the reactivation of the latently infected recipient’s own virus despite pre-transplantation humoral immunity. These findings suggest the conclusion that antiviral antibodies are inefficient in controlling CMV. Rather than B cells and antibodies, T cells, in particular CD8 T cells, are thought to play a major role in resolving established organ infection. In theory, antibodies, though being capable of neutralizing free virions, could fail to prevent cell-bound virus dissemination from the portal of entry to distant target tissues and also could fail in preventing cell-to-cell spread within tissue. Here we have used murine model systems, including B cell deficient C57BL/6 μ⁻ μ⁻ (μMT) mutants, to revisit the role of antiviral antibodies in the control of CMV infection and to reevaluate the prospects of an antibody-based immunotherapy from a basic science point of view.