In humans, the rate and clinical expression of disease in congenitally cytomegalovirus (CMV)-infected infants is modified by maternal immunity to CMV. We used the guinea pig model of congenital CMV infection to compare maternal CD4+ T-cell numbers in nonpregnant animals to those in pregnant dams just before and 7-14 days after inoculation with guinea pig CMV (gpCMV) very early, early, or late in gestation. We also examined ELISA antibody responses to gpCMV in the inoculated nonpregnant and pregnant animals. When compared to nonpregnant uninfected animals, CD4 counts were lower in very early and in late uninfected gestation. CD4 counts also dropped further in the postinoculation period. Compared to nonpregnant gpCMV-inoculated animals, initial antibody responses to gpCMV were also decreased in gpCMV-infected pregnant dams. The group of dams inoculated very early in pregnancy experienced delays in seroconversion to gpCMV, persisting low titers throughout gestation, in utero fetal resorptions, and CNS-infected pups. The group of dams inoculated late in gestation had the lowest geometric mean titers at delivery (almost 50% with no detectable antibody) and a high rate of vertical gpCMV transmission and postnatal pup death. Significantly lower rates of both congenital infection and postnatal pup deaths were observed in litters of late gestation-infected dams that had gpCMV antibody at delivery. Thus, decreased circulating maternal CD4+ T cells very early and late in gestation were further decreased after gpCMV inoculation and were associated with delayed and depressed maternal antibody responses, all of which were associated with poor outcome after primary maternal gpCMV infection, the expression of which varied by time in pregnancy when gpCMV was acquired.