In October 1992, Haemophilus influenzae type b (Hib) conjugate vaccine was introduced to infants in the United Kingdom with a "catch-up" program for those aged <4 years. Initially, the rate of invasive Hib disease decreased dramatically but has been increasing since 1999. To determine possible reasons for this increase, the effectiveness of Hib conjugate vaccine was estimated by use of the screening method. Between October 1993 and December 2001, a total of 443 cases of Hib infection occurred in children eligible for vaccination; 363 (82%) were fully vaccinated. Vaccine effectiveness was estimated to be 56.7% (95% confidence interval, 42.5-67.4). Effectiveness was lower in children vaccinated during infancy, compared with those who were vaccinated during the catch-up campaign (P=.0033), declined with time since vaccination (P=.0008), and was lower in children born during 2000-2002, compared with other children scheduled for infant vaccination (P=.0041). Use of a catch-up vaccination program enhanced the control of Hib infection in England and Wales. Since 1999, however, low effectiveness in infants, declining effectiveness with age, and the use of lower-efficacy vaccines have contributed to increased rates of Hib infection. The potential role of boosters needs to be considered.