The incidence of invasive Haemophilus influenzae type b (Hib) infection was decreased significantly among Navajo children since the licensure of Hib conjugate vaccines, even though two lots of Hib (polyribosylribitol phosphate)-meningococcal B outer-membrane protein conjugate vaccine (PRP-OMP) widely used among the Navajo were later found to be of low immunogenicity. We measured the effectiveness of all Hib conjugate vaccines combined, PRP-OMP alone, and the PRP-OMP lots with lower-than-expected immunogenicity among Navajo infants and children. This was a matched case-control study using active, laboratory-based surveillance for the ascertainment of Navajo children 2 1/2 to 59 months of age with invasive Hib infection; 45 patients with infection and 180 control subjects were enrolled. The effectiveness of one, two, and three doses, respectively, of all Hib conjugate vaccines combined was 96% (95% confidence interval (CI) 65%, 99%), 99% (95% CI, 69%, 100%), and 99% (95% CI - 57%, 100%). The effectiveness of one or more doses of PRP-OMP was 95% (95% CI, 66%, 99%). The effectiveness of a single dose of the lots of lower-than-expected immunogenicity was 89% (95% CI, -8%, 99%). The Hib conjugate vaccine coverage increased from 49% during 1991 to 94% during 1992; no control subjects younger than 18 months of age were enrolled during 1993. The occurrence of invasive Hib infections in this population after licensure of Hib conjugate vaccines was the result of gradual vaccine uptake, not poor vaccine effectiveness. The use of PRP-OMP has been highly effective despite concerns about the immunogenicity of several lots.