Infant vaccination with conjugated Haemophilus influenzae type b (Hib) vaccine is highly effective in protecting against invasive Hib infections, but vaccine failures do occur. Twenty-one vaccine failures are reported since the introduction of the Hib conjugate vaccine in The Netherlands. Of the 14 evaluable patients, 6 children showed no antibody response to Hib polysaccharide in convalescent-phase serum (immunoglobulin [Ig] G anti-Hib level <1.0 microg/mL), including 1 child with hypogammaglobulinemia and 1 child with IgG2 deficiency. After revaccination, almost all children developed anti-Hib antibodies. In case of Hib vaccine failure, case investigation should be performed, including measurement of serum Ig concentrations as well as specific anti-Hib antibodies. Invasive Hib disease after infant conjugate Hib vaccination may be the presentation of an underlying immunodeficiency, but more often, only a decreased antibody response to Hib is found; revaccination with conjugated Hib vaccine is advised.