We examined the ability of severe combined immunodeficient (SCID) mice-human peripheral blood leukocyte (PBL) chimeras to respond to immunization with Haemophilus influenzae b polysaccharide (Hib PS) vaccines. Two to 3 wk after PBL engraftment, human-PBL-SCID mice, prepared with PBL from one of five adult donors, were immunized with free or protein-conjugated Hib PS. Antibody to Hib PS was quantitated in preimmunization and postimmunization sera. Before immunization, anti-Hib PS antibody was detectable (>10 ng/mL) in three of 40 mice. Of the 37 human-PBL-SCID mice not having detectable serum antibody before immunization, 31 produced ≥20 ng/mL (≥2-fold increase) anti-Hib PS antibody 2 to 3 wk after immunization. Both free and protein-conjugated forms of Hib PS were immunogenic. Geometric mean anti-Hib PS antibody levels ranged from 50 to 139 ng/mL. Vaccine-induced anti-Hib PS antibodies frequently expressed Hibld-1, a cross-reactive idiotype that predominates the in vivo human antibody response to Hib PS. However, among mice engrafted with PBL from a single donor, the Hibld-1 distribution was highly skewed, suggesting that clonally distinct B cells were being stimulated in individual mice. These findings indicate that human PBL transplanted into SCID mice are functionally responsive to Hib PS antigenic challenge. This system may serve as a useful model for studying the regulation and cellular requirements for human polysaccharide immunity.