Background. Before 7-valent pneumococcal conjugate vaccine (PCV7) introduction, invasive pneumococcal disease (IPD) rates among Navajo were several-fold those of the general US population. Only 50% of IPD cases in children involved PCV7 serotypes. Methods. We conducted active, population-based surveillance for IPD for the period 1995-2006. We documented case characteristics and serotyped the isolates. Results. Over 12-year period, we identified 1508 IPD cases, 447 of which occurred in children aged < 5 years. Rates of IPD due to vaccine serotypes among children aged < 1 year, 1 to < 2 years, and 2 to < 5 years decreased from 210, 263, and 51 cases per 100,000 population, respectively in 1995-1997 to 0 cases in 2004-2006 (P < . 001). Among adults aged >= 65 years, rates of IPD due to vaccine serotypes decreased 81% (95% confidence interval, -98% to -9%; P = .02). Rates of nonvaccine serotype IPD were unchanged in all age strata except for persons aged 18 to < 40 years, among whom the rate decreased by 35% from 27 to 18 cases per 100,000 population (95% confidence interval, -57% to -1%; P = .03). Conclusions. Vaccine-serotype IPD has virtually been eliminated in the PCV7 era among Navajo of all ages. Overall rates of nonvaccine-serotype IPD have not increased, although increases have occurred for some individual types. Rates of all-serotype IPD among Navajo children remain 3-5-fold greater than in the general US population.