In a previous study we demonstrated that Alaskan Eskimos had the highest endemic incidence of invasive Haemophilus influenzae type b (Hib) disease. In 1980 we established a prospective surveillance program for all invasive Hib disease throughout Alaska to characterize additional epidemiological features of disease in Native Alaskans to plan for a vaccine efficacy trial and define the epidemiology of Hib disease in all population groups in the state. For the three-year period, 1980-1982, 287 confirmed episodes of invasive Hib disease occurred. For children less than five years of age, the incidences for Eskimos, Indians, and non-Natives were 705, 401, and 129 cases per 100,000 population, respectively. The Native population represents only 16% of the population of Alaska but has 51% of all invasive Hib disease. Disease differed significantly among Eskimos, Indians, and non-Natives with regard to risk, age of onset, disease type, antibiotic susceptibility of strains, and regional incidence, but mortality and seasonal occurrence were similar. For Native Alaskans the cumulative Hib disease risk for the first two years of life was 4% (range, 1%-7% by region). This high endemic disease risk, concentrated in the first two years of life, provides a unique opportunity to prospectively evaluate the protective efficacy of a vaccine in a randomized, blinded, and placebo-controlled trial. Such a trial was initiated in December 1984.