The humoral immune response against human cytomegalovirus (CMV) was retrospectively investigated in >800 serum samples from 31 recipients of allogeneic bone marrow transplants. To this end, an ELISA was performed that allowed the individual analysis of IgG antibodies against known antigenic domains of CMV-derived phospho- and glycoproteins and nonstructural polypeptides. Twenty-nine patients developed active CMV infection after transplantation, as determined by repeatedly positive samples in polymerase chain reaction (PCR) assays. Seventeen patients responded serologically to viral replication by producing CMV-specific antibodies against a variety of antigens. The response was detectable concomitantly with PCR positivity and was seen as early as 20 days after transplantation. High titers of glycoprotein-specific neutralizing antibodies were correlated with the absence of viral DNA in blood (P < .002). Nineteen patients developed CMV disease. Survival was associated with the production of high titers of CMV glycoprotein-specific antibodies in response to viral replication.