Human immune serum globulin (ISG) preparations were tested in an in vivo suckling rat protection assay and an in vitro opsonophagocytic assay against various types and strains of Group B streptococci (GBS). Standard ISG provided minimal protection in suckling rats against type III GBS sepsis, whereas preparations of ISG modified for intravenous administration (MISG) provided significant protection against all strains of type III, type II and type Ia GBS tested. Although less protection was obtained against type Ia strains, the survival in suckling rats challenged with all types of GBS varied from 73% to 91% with MISG therapy, as compared with 5% to 12% survival in untreated animals. In this in vivo model, MISG was protective even when administered after bacterial challenge, but had to be administered within 5 h of infection. MISG also had high in vitro opsonic activity against GBS types III and II, but was less effective with some type Ia strains. Just as MISG was more protective than ISG in vivo, it also was more opsonic in vitro. A detailed comparison of one lot of MISG with its parent ISG revealed that the modified preparation actually contained less IgG. When equivalent concentrations of affinity-purified IgG from both preparations were tested, the IgG from MISG was significantly more opsonic. Since the affinity purification procedure eliminated the possibility that IgM or substances introduced in the modification process were actually responsible for the enhanced bactericidal activity, it appears that the individual IgG molecules in MISG may be more effective. These studies suggest that MISG which has been modified by reduction and alkylation for intravenous administration may provide a valuable adjunct to chemotherapy in the treatment of GBS disease in the neonate.