From January 1986 through December 1990,672 cases of invasive pneumococcal disease were identified. From these, 574 pneumococcal isolates were recovered from normally sterile sites (blood, cerebrospinal and pleural fluid); 92% were serotypes represented in the 23-valent pneumococcal polysaccharide vaccine. The most common serotypes from children <2 years old were 4, 6B, 9V, 14, 18C, 19F, and 23F, recovered from 83% ofAlaska Native and 75.1%ofnonnative children with invasive disease. Moderate penicillin resistance (MIC, 0.1-1.0 “”g/mL) was found in 3.8% of isolates. All were sensitive to chloramphenicol, vancomycin, rifampin, ceftriaxone, cefotaxime, cephalothin, and cefaclor. However, in the Yukon-Kuskokwim Delta region, 16.9% of isolates were moderately resistant to penicillin, and 10.8% were resistant to erythromycin and 6.2% to trimethoprim-sulfamethoxazole; the number resistant to two or more antibiotics increased significantly during surveillance. All multiply resistant isolates were serotype 6B, and all were from Alaska Native patients < 2 years old.