A prospective study of the virology of and serological responses to enterovirus infection in 16 neonates (< or = 2 weeks of life) and their mothers was performed. At study entry, 11 neonates did not have detectable serum neutralizing antibody to their own viral isolates, despite the presence of neutralizing antibody in 9 of 11 mothers of these infants. Viremia and viruria were demonstrated in 8 and 7 neonates, respectively, with maximal detected titers of 6.3 x 10(3) 50% tissue culture infective dose per mL (TCID50) and 6.8 x 10(1) TCID50/mL, respectively. Viremia was associated with onset of illness in the first 5 days of life, low initial serum neutralization titer, and the presence of echovirus serotypes. Randomized administration of intravenous immune globulin (IVIG; 750 mg/kg) to nine neonates overall modestly increased serum neutralization titers but did not reduce the daily incidence of viremia and viruria compared with that of controls. However, receipt of IVIG containing a neutralization titer of > or = 1:800 to the patients' own viral isolates was associated with significantly higher serum neutralization titers and more rapid cessation of viremia and viruria. Future trials of IVIG for neonatal enterovirus disease should assess the efficacy and safety of higher or repeated doses of this agent and/or of IVIG selected for their high titers to frequently circulating and/or particularly virulent enterovirus serotypes.