Twenty-six healthy children previously immunized (imm) with the Hib capsular polysaccharide (Hib CP) vaccine at age 19 to 38 mos (GM=28 mos; 1 of 26 <24 mos) developed Hib systemic disease at age 22 to 45 mos (GM=32 mos), which was 2 to 44 wks (GH=12.6 wks) after imm. Disease consisted of 16, 6, and 4 cases of meningitis, epiglottitis, and other infections, respectively. Antibody (Ab) to the Hib CP in serial convalescent serum samples collected 24 days-8 mos after infection failed to increase to 1μg/ml in 17 Of the 26 and had a GMT of 0.56μg/ml, which contrasted with Ab of an age-matched control group of Hib infected, nonimm children (GMT=2.7μg/ml, p<.05). IgG2 subclass deficiency was detected in 9 of the 26 and was associated with low or borderline-low levels of IgG and IgA in 5 and 6 of the 9 respectively. Postinfection Ab to the Hib CP was <1 μg/ml in 7 of the 9 with IgG2 deficiency (GMT=0.29μg/ml), but all had normal Ab titers to tetanus and diphtheria toxoids. At present, reimm with the Hib CP and imm with pneumococcal CPs induced poor Ab responses in 1 of 1 and 3 of 3 with IgG2 deficiency, respectively. These findings suggest that a considerable proportion of cases of this new entity - Hib disease after Hib CP imm - is associated with IgG2 subclass deficiency and poor Ab responses to Hib infection.