The prenatal and perinatal transmission of maternal cytomegalovirus (CMV)-specific immunity was studied in the guinea pig by cross-fostering newborns of seropositive and seronegative mothers. Resistance to CMV was assessed by challenging the newborn and adult offspring with sublethal doses of CMV and following the course of their acute CMV disease. Newborns were found to acquire detectable CMV antibody via the placental route but not the breast milk route. When compared to neonates with no acquisition of CMV immunity, neonatal offspring born to or foster fed on seropositive mothers were protected against generalized CMV infection to various degrees. The immunity transferred by pregnant mothers that had seroconverted prior to pregnancy was short lived and was more protective in newborns with detectable CMV antibody. Mothers that experienced primary CMV infection during pregnancy conferred on their progeny the most significant and long-lasting resistance against CMV challenge. This study demonstrates that newborn guinea pigs may acquire CMV-specific immunity from seropositive mothers; the degree of protection against CMV infection depends on the route of acquisition of immunity and on the time of maternal seroconversion.