We report an enhanced prospective survey of invasive Haemophilus influenzae infections that has defined the pattern of invasive disease in five English regions for 2 years before and 4 years after the introduction of the H. influenzae type b (Hib) vaccination program. During the prevaccination period the majority of cases of invasive H. influenzae were caused by type b; most (89%) of these infections occurred in children <5 years of age and the most common presentation was meningitis. Since the introduction of routine immunization of infants with conjugate Hib vaccine, there has been a 16-fold reduction in the annual attack rate of invasive Hib disease recorded in children <5 years of age. This reduction is of a magnitude similar to that observed in other countries with Hib vaccination programs. The number of infections caused by non-type b H. influenzae has shown a small but progressive increase over the same period, emphasizing the need for continued surveillance. There was no increase in the number of infections caused by other serotypes. Diagnostic category varied with both age and serotype but was not affected by vaccine introduction; meningitis was the most common presentation overall but pneumonia and bacteremia were more common in adults and with noncapsulated isolates.