Staphylococcus epidermidis is a major cause of nosocomial infections, including sepsis in premature infants. Intravenous immune globulin (IVIG) has been used to prevent neonatal sepsis, but efficacy has varied in different clinical trials. The role of IgG antibody in immunity to S. epidermidis was studied using an opsonophagocytic assay and a lipid-emulsion-induced lethal model of neonatal S. epidermidis sepsis. Opsonic antibody to S. epidermidis varied between IVIG preparations and between lots: Lots with > or = 90% opsonic activity promoted bacterial clearance from blood and significantly enhanced survival when compared with lots with < or = 50% opsonic activity. Absorption of IVIG with S. epidermidis removed in vitro opsonic and in vivo protective activity. These studies suggest that opsonic antibody may play an important role in S. epidermidis immunity in immunocompromised patients, such as premature infants. Standard IVIG, however, may not provide therapy effective in preventing S. epidermidis infections, as many IVIG lots contain insufficient levels of opsonic S. epidermidis antibody.