High rates of invasive pneumococcal disease have been described among infants living in various Native American communities. In this study, we evaluated the immunogenicity of a 7-valent pneumococcal vaccine consisting of serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F covalently linked to the outer membrane protein complex of Neisseria meningitidis in Apache and Navajo Indian, Alaska Native, and non-Native American children. The vaccine was administered at ages 2, 4, and 6 months; a booster dose was given at age 15 months. Levels of serotype-specific immunoglobulin G (IgG) were measured by a standardized enzyme-linked immunosorbent assay. The responses after 3 primary doses of vaccine were similar in all 3 groups of children, except for those to serotypes 14 and 23F. One month after the booster dose, geometric mean concentrations (GMCs) of serotype-specific IgG antibodies increased significantly in all 3 groups of children, compared with GMCs of IgG antibodies to pneumococcal serotypes before the booster dose.