We studied 55 cases of invasive Hemophilus influenzae type b disease occurring in children at least three weeks after vaccination with type b polysaccharide vaccine. Their mean age at the time of immunization was 27.8 months (range, 18 to 47). Meningitis developed in 39 patients, of whom 3 died and 6 had neurologic sequelae. We investigated certain host factors that may have contributed to the failure of the vaccine. The geometric mean concentration of antibody to type b polysaccharide in convalescent-phase serum from 31 of the vaccinated patients who had hemophilus disease was significantly lower than that in serum from 25 patients of similar age with the disease who had never been vaccinated (0.59 vs. 3.46 μg per milliliter, P<0.001). However, only 3 of 46 patients in whom the vaccine failed and who were tested for hypogammaglobulinemia had this finding, and none of 33 children tested for IgG2 had low serum concentrations of this immunoglobulin subclass, which is thought to be important in the immune response to polysaccharide antigens. In addition, all but 1 of the 46 patients in whom the vaccine failed and who were tested for IgG antibody to tetanus toxoid protein, a thymic-dependent antigen, had normal values, and 19 of 20 tested for hemolytic complement activity had normal levels. In white children, the presence of the Gm immunoglobulin phenotype (1,2,3,17;;5,13,21) was associated with a sevenfold increase in the relative risk of vaccine failure (P<0.003). We conclude that vaccine failure may be related in part to genetic factors, and that most vaccinated children in whom Hemophilus influenzae disease develops have deficient antibody responses to the type b polysaccharide despite normal serum concentrations of immunoglobulin and normal antibody responses to tetanus toxoid. (N Engl J Med 1986; 315:1584–90.), HEMOPHILUS influenzae type b polysaccharide vaccine was licensed in the United States in April 1985. In a field trial in Finland, the vaccine was 90 percent effective in preventing disease in children immunized between 24 and 71 months of age.1,2 It had no efficacy in children younger than 18 months, and uncertain efficacy in children 18 to 23 months old.3 In the United States, the vaccine is recommended for all children 24 to 59 months of age.4 In addition, the Advisory Committee on Immunization Practices, but not the American Academy of Pediatrics, recommends immunization of children 18 to 23 months… © 1986, Massachusetts Medical Society. All rights reserved.