Group B streptococcal (GBS) infections continue to be a major cause of morbidity and mortality in human neonates. This has led a number of investigators to explore the role of immunotherapy in the treatment of neonatal GBS disease. In early studies, we showed that intravenous immune globulin (IVIG) offered some protection against less virulent strains of GBS in a neonatal rat model of disease. Against more virulent strains, which produce an excess of sialic acid-containing type-specific antigen, IVIG offered little protection even when given in much higher doses. For this reason, we developed murine monoclonal antibodies (MuMAb) against type III GBS. MuMAb directed against the type III-specific antigen provided excellent protection against virulent (greater than 95%) and less virulent (94-100%) strains of GBS when administered in doses as low as 400 micrograms/kg up to 24 hr after bacterial inoculation. MuMAb IgM antibody was approximately 100-fold more effective than MuMAb IgG2a antibody. Unfortunately, MuMAbs are unlikely to be approved for use in human neonates. For this reason, we have evaluated a human monoclonal antibody (HuMAb) preparation against GBS derived from Epstein-Barr virus-immortalized peripheral blood B lymphocytes. This IgM HuMAb, which appears to be directed against the group B carbohydrate, is extremely active in both opsonic and protective assays against type Ia, II, and III GBS. Optimal immunotherapy of neonatal GBS disease may involve the use of HuMAb preparations, alone or in combination with polyclonal IVIG.