Relatively penicillin-resistant pneumococci have caused 10% of invasive pneumococcal disease in central Oklahoma during the last decade, but almost no high-level penicillin or other antibiotic resistance has been described. This study evaluated antibiotic susceptibility and serotype distribution in invasive pneumococcal disease in the Oklahoma City metropolitan area (1990 population 848,000). A total of 144 cases of invasive infection was collected in 1 year (17 with meningitis, 120 with other bacteremic infections, and 7 with other invasive infections), for a rate of 16.9/100,000 (95% confidence interval [CI], 14.0-19.5). For the population aged > or = 60, invasive pneumococcal disease rates were higher among nursing home residents (352/100,000) than among nonresidents (25.6/100,000; relative risk, 13.7; 95% CI, 7.7-24.7). Antibiotic-resistant organisms caused 19.4% of the cases: relative penicillin resistance, 7.6%; high-level penicillin resistance, 1.4% (2 cases), and 11% resistance to erythromycin, trimethoprim-sulfamethoxazole, or both, with 5% sharing both resistances plus a MIC of penicillin of 0.06 microgram/mL.