A prospective study of newborn infants who required exchange transfusion was undertaken to evaluate the risk of transmission of cytomegalovirus (CMV). Buffy coat-, urine- and saliva-saturated throat swabs for viral cultures and serum specimens for CMV complement-fixing (CF) antibody were obtained from 45 infant-mother pairs. Buffy coat from the donor blood was cultured and CMV CF titers measured. Viral studies were repeated on infants and mothers at six and 12 weeks after exchange transfusion. Fifteen infants received CMV seropositive blood and 14 infants received CMV seronegative blood. Sixteen infants who did not receive blood or blood products served as controls. Three of 12 antibody-positive newborns developed infection after getting seropositive blood. One of three antibody-negative newborns developed infection after getting seropositive blood. The presence of transplacental antibody does not appear to protect the infants. None of the control infants developed CMV infection. None of the infected infants were symptomatic. Although CMV infection in infancy can be acquired by routes other than blood, exchange transfusion with seropositive blood enhances the likelihood of acquiring infection.