Invasive pneumococcal disease occurs 2-3-fold more often among Navajo adults than among adults in the general United States population. The objective of this observational study was to determine the effectiveness of the 23-valent pneumococcal polysaccharide vaccine (PPV23) among Navajo adults. Active surveillance identified cases of invasive pneumococcal disease during 1996-1997. Three control patients per case patient were matched according to underlying medical conditions, sex, age, and location of medical care. Effectiveness was calculated by regression analysis of case-control sets and by indirect cohort methodology. Diabetes and alcoholism occurred in 41% and 43% of 108 case patients, respectively; 62% of case patients and 64% of control patients were immunized. Overall vaccine effectiveness was 26% (95% confidence interval [CI], -29% to 58%); 15% (95% CI, -116% to 67%) for patients with diabetes and -5% (95% CI, -141% to 54%) for patients with alcoholism. Overall vaccine effectiveness, as determined by use of the indirect cohort methodology, was 35% (95% CI, -33% to 69%). PPV23 was not significantly effective among Navajo adults and may be inadequate to prevent serious pneumococcal disease in this population.