Compared with white and black persons in the United States, some Native American groups are at increased risk for invasive pneumococcal disease (IPD). To characterize the epidemiology of IPD among Navajo adults, we conducted active surveillance for IPD on the Navajo Nation and reviewed medical records of patients with IPD. For 1997-1998, the annual incidence (cases per 100,000 persons) was 56 for Navajos aged 18-64 years and 190 for Navajos aged > or =65 years. The corresponding rates were 10 and 57 for white and 44 and 82 for black persons in the United States. The case-fatality rate was 14%. Eighty percent of cases were caused by serotypes included in the 23-valent pneumococcal polysaccharide vaccine. Navajo adults have rates of IPD that are 3-5-fold higher than those of the general US population. Additional research is needed to understand the reasons for this elevated risk and to develop prevention strategies.