Streptococcus pneumoniae is the most common cause of invasive bacterial disease among children worldwide. The authors aimed to determine the incidence, clinical characteristics, and serotype distribution of invasive pneumococcal disease (IPD) among Navajo children in the southwestern United States. Active population-based laboratory surveillance for IPD among resident members of the Navajo Nation under 18 years of age was conducted between 1989 and 1996. During this 8-year period, 706 cases of IPD were identified. The rate of disease varied by age, with the highest rate being observed among children aged 6-11 months (727 cases/100,000 person-years), followed by children aged 0-11 months, 0-23 months, and 0-59 months (568, 537, and 272 cases/100,000 person-years, respectively). Among children aged 0-23 months, 60.3% of cases were caused by serotypes in the seven-valent conjugate pneumococcal vaccine (71.5% from 1989-1993 and 58.3% from 1994-1996). Navajo children are at increased risk of IPD in comparison with the general US population. The distribution of disease-causing serotypes is similar to that of many countries in the developing world. Prevention strategies should include the use of licensed pneumococcal protein conjugate vaccine; however, a substantial proportion of disease is caused by nonvaccine serotypes. These data are critical for assessing the impact of these vaccines in this high-risk population.