Patients with the hyper-IgE (HIE) syndrome have recurrent bacterial infections with Staphylococcus aureus and other polysaccharide encapsulated organisms. To determine whether an impairment of the antibody response to polysaccharide antigens contributes to infections in this syndrome, we measured serum antibody to the teichoic acid of S. aureus and to the capsular polysaccharide of Haemophilus influenzae type b. Compared to control subjects who had no history of S. aureus infections (N = 14), sera from patients with HIE (N = 9) lacked the expected elevation of serum antibody to teichoic acid (p greater than 0.05) and had significantly lower levels of this antibody than sera from 14 patients with atopic dermatitis, complicated by recurrent cutaneous S. aureus infections (p less than 0.01). After immunization with the capsular polysaccharide of Haemophilus influenzae type of vaccine, the antibody response of patients with HIE was significantly impaired compared to that of age-matched control subjects (p = 0.01). Although patients with HIE syndrome had normal total IgG levels, most patients with HIE but not patients with atopic dermatitis had IgG2 subclass deficiency. Defective antibody responses in patients with HIE were not restricted to polysaccharide antigens because the serum levels of antitetanus toxoid antibody in these patients were significantly lower than that of control subjects (p less than 0.001). Impaired antigen-specific antibody responses in patients with HIE syndrome may contribute to their increased susceptibility to infection.