Viral excretion, antibody response, and specific cell-mediated immunity were studied in 104 children with congenital cytomegalovirus (CMV) infection followed from birth. The study population demonstrated prolonged viral shedding and stable, moderate levels of serum antibody. The majority of patients ceased salivary shedding of CMV by two years of age but continued to have viruria through the fifth year. Patients who had symptomatic infection or CNS sequelae were similar to asymptomatic patients with regard to both viral excretion and antibody response. Although symptomatic patients had significantly weaker specific blastogenic responses from one to seven years of age, the majority of patients from both groups had no detectable response to CMV through their fifth year. The impairment was highly specific for CMV, as patients with congenital CMV infection who had antibody to herpes simplex virus did have a lymphocyte blastogenic response to the latter virus. Although specific lymphocyte blastogenesis did not correlate with outcome, the presence of a positive response was associated with cessation of viruria.