Human cytomegalovirus (HCMV)-specific antibody responses in HIV-1 infected individuals either with or without HCMV end-organ disease were examined to determine the whether development of HCMV disease was associated with a particular deficit in the antibody response. Antiwhole HCMV, anti-glycoprotein B (gB), and neutralizing antibody levels were higher in HIV-1 infected individuals than in healthy immunocompetent subjects, particularly in patients with AIDS either with or without HCMV-associated disease. Irrespective of location and spread of HCMV disease, patients who had received anti-HCMV therapy prior to sampling exhibited significantly higher anti-gB and neutralizing antibody titers than those who remained untreated. Likewise, patients with HCMV disease who were antigenemic or viremic had significantly lower anti-gB and neutralizing antibody titers than those who tested negative in either assay. Patients with untreated HCMV disease had significantly lower antibody titers than AIDS patients without disease. Analysis of the IgG subclass antibody responses to gB revealed no significant differences among HIV-1 infected individuals. These results suggest that levels of detectable anti-gB and HCMV neutralizing antibodies are inversely related to systemic viral load. Thus, antibodies with such specificities may be relevant in preventing the establishment of HCMV-associated disease or in modulating its progression.