We determined serial IgG antibody responses to cytomegalovirus (CMV)-encoded proteins in sera collected over a one-year interval from 14 subjects with CMV mononucleosis. Antigens from infected human fibroblasts included three components: cytoplasmic, nuclear, and high-speed pellet. Antibody was detected by radioimmunoprecipitation followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Twenty to 21 bands were observed with the cytoplasmic component, whereas 10 and 9, respectively, were seen with the nuclear and high-speed pellet antigens. The most intense reactions occurred with the higher-molecular-mass proteins (50-215 kDa) by using the cytoplasmic and high-speed antigens and with the more rapidly migrating proteins (less than 50 kDa) by using the nuclear antigen. The precipitin responses increased for three months or more after onset of symptoms with the nuclear and high-speed pellet antigens but peaked within one to two months with the cytoplasmic antigen.