Alaska Native persons have age-adjusted invasive pneumococcal disease (IPD) rates two- to three-fold greater than non-Native Alaskans. To characterize IPD epidemiology and 23-valent polysaccharide pneumococcal vaccine (PPV-23) effectiveness in Alaska Native adults we reviewed IPD cases from Alaska-wide, laboratory-based surveillance. Sterile site isolates were serotyped. Vaccine effectiveness (VE) was estimated using the indirect cohort method. 394 cases (44.5 cases/100,000/year) occurred in 374 Alaska Native adults (36.0% aged > or =55 years). Underlying conditions included heavy alcohol use (65.7%), smoking (60.8%) and COPD (25.0%). Overall VE was 75% (95% confidence interval [CI]: 27%, 91%) but declined with increasing age; for persons > or =55 years (VE=<0; 95% CI: <0, 78%; p=0.713). Alaska Native adults experience high rates of IPD. The majority of IPD cases occurred in persons with underlying conditions and behaviors associated with increased risk of IPD in other populations. PPV-23 vaccine effectiveness was confirmed in younger Alaska Native adults but not among adults > or =55 years.