Haemophilus influenzae infection causes serious invasive disease, but incidence of the most virulent serotype, Hib, has dropped since introduction of routine Hib vaccination. In England and Wales, the incidence of 2 other serotypes, Hie and Hif, is increasing; during 2001-2010, there was an 11.0% year-on-year increase in Hif and a 7.4% increase in Hie. In 2009-2010, Hif incidence was 0.090/100,000 persons and Hie incidence 0.030/100,000, with higher rates among infants and older adults. Hie had a more severe clinical course; although outcome at 6 months was comparable for the 2 serotypes, case-fatality rate within 7 days of diagnosis was higher for Hie, even after adjustment for age and comorbidities. Multilocus sequence typing revealed a single major circulating clone for both Hif (sequence type 124; 89/99 isolates, 90%) and Hie (sequence type 18; 21/33, 64%), but no association between type and clinical disease or outcome was found.