To characterize more fully the immunologic basis for increased susceptibility to infection in patients with low serum concentrations of IgG2, we identified eight infection-prone children, 1 to 2 years of age, with serum IgG2 concentrations >2 SD below the mean for age and followed their serologic and clinical courses for 1 to 3 years. Two of the eight children became clinically and immunologically normal and may have had transient IgG2 deficiency with an exaggerated developmental delay of this late-maturing subclass. The remaining six subjects had persistently subnormal or low-normal serum IgG2 levels and continued to experience frequent infections. All six of these children responded poorly to Haemophilus influenzae type b (Hib) polysaccharide, and four of six responded poorly to Streptococcus pneumoniae type 3 polysaccharide. Both IgG1 and IgG2-specific antibody responses to these vaccines were abnormal. Three of these six children also responded poorly to tetanus toxoid, an antigen that normally induces a predominant IgG1 response. Although five of these six children produced antibodies in response to Hib polysaccharide protein conjugate vaccine, three of four given Hib oligosaccharide CRM conjugate vaccine required booster doses to respond, a pattern of response characteristic of infants <6 months of age. Further, although serum concentrations of IgG1 were normal, peripheral blood mononuclear cells from four of six children tested produced extremely small amounts of IgG1 and IgG3 as well as IgG2. Finally, varied patterns of abnormalities of IgG, IgA, IgM, and IgG4 became apparent in five of the six children with persistently low serum IgG2 values. This study demonstrates that subnormal serum concentrations of IgG2 may be associated with varied patterns of immunologic dysfunction, some of which are evolving and may be responsible for increased susceptibility of these children to infection.