Antibody avidity to Haemophilus influenzae type b (Hib) polysaccharide (PS) was assessed in infants vaccinated with diphtheria-tetanus-acellular pertussis (DTaP) combined with Hib-PS conjugated to tetanus toxoid (PRP-T) and hepatitis B (HB) (DTaP-PRP-T-HB) and after a PRP-conjugate (CRM197-OS) booster 3-7 months later. Avidity differed between infants with anti-Hib-PS IgG antibody <1 or >1 microg/mL postprimary series (avidity index [AI], 42%, 95% confidence interval [CI], 35%-49%, and 68% and 63%-72%, respectively; P<.0001). For infants with <1 microgram/mL anti-Hib-PS IgG antibody, mean AI rose by the time of preboost immunization to 61% (95% CI, 57%-65%), even though total IgG antibody levels fell. Spontaneous Hib-PS antibody rises after primary series DTaP-PRP-T-HB vaccination were followed by high postboost anti-Hib-PS IgG antibody levels and avidity. The DTaP-PRP-T-HB combination vaccine studied elicits high avidity antibody, and affinity maturation appears to occur in the absence of further antigen exposure even in those with very low anti-Hib-PS antibody.