To investigate whether an underlying defect in antibody (Ab)-forming capacity could contribute to the infection susceptibility of patients with hyper-IgE syndrome, we evaluated 11 such patients for their responses to bacteriophage phi X174 (phi X174), diphtheria and tetanus toxoids, and pneumococcal (Pneumovax) and Hemophilus influenzae vaccines. Three of nine patients immunized with phi X174 had normal primary and secondary Ab responses, five had accelerated declines in their titers after initially normal primary Ab responses and lower than normal secondary Ab responses, and two of the latter patients failed to switch normally from IgM to IgG Ab production. Only one of 10 patients tested had normal Ab responses to diphtheria toxoid, and postimmunization antitetanus titers were abnormally low in five of the 10 patients tested. Serum Abs to H. influenzae polyribose phosphate were protective in seven of the eight immunized patients. Five of the nine patients administered Pneumovax had poor Ab responses to at least one of the pneumococcal serotypes 7, 9, or 14. Abnormal antipolysaccharide responses did not correlate with IgG2 deficiency. All patients responded with protective Ab levels to type 3. Thus, patients with hyper-IgE syndrome are heterogeneous with respect to their Ab-forming capacities. Ab deficiency may contribute to infection susceptibility in some of these patients.