Intravenous immunoglobulin replacement is recommended for immunoglobulin deficiency, but comparison of the efficacy of intravenous immunoglobulin preparations (IVIGs) has been hindered by the lack of standardized assays to measure immunoglobulin levels against important bacterial pathogens. IgG reactive with five commonly isolated serotypes of Streptococcus pneumoniae in four commercially available IVIGs was measured by ELISA. Specific antibody to capsular polysaccharide was quantitated before and after adsorption with cell wall polysaccharide (CWPS). All IVIGs contained measurable levels of antibody to the five pneumococcal serotypes, although the levels against an individual serotype varied by as much as sevenfold from one preparation to another. Each IVIG also contained substantial concentrations of IgG reactive with CWPS. The amount of each IVIG that protected mice was nearly identical after the doses were adjusted on the basis of specific IgG measured by ELISA, thereby providing proof in vivo of the validity of this in vitro assay system.