Human cytomegalovirus (HCMV)-specific antibody responses after primary maternal infection were examined to determine if specific deficits in antibody response were associated with intrauterine transmission. Anti-glycoprotein B IgG antibodies were significantly higher at delivery in transmitters than in nontransmitters, suggesting that the amount of antiviral antibody was not reflective of protection from transmission. Characterization of the qualitative antibody response revealed lower neutralizing antibody titers in transmitters, suggesting an association between neutralizing activity and intrauterine transmission. Examination of anti-HCMV antibody avidity revealed that the majority of nontransmitters but <20% of transmitters had an avidity index =2.0 (P <.002). A significant correlation between neutralizing titers and antibody avidity was demonstrated. Thus, antibody affinity maturation is critical for production of high levels of neutralizing antibodies during primary HCMV infection, and a defect in affinity maturation may playa role in intrauterine transmission of HCMV. © 1995 by The University of Chicago.