The increasing number of Streptococcus pneumoniae isolates identified as relatively or fully resistant to penicillin or fully resistant to other antimicrobials in the United States supports the need to monitor for this resistance. Thus, 5459 S. pneumoniae isolates submitted to the Centers for Disease Control in 1979-1987 by 35 hospitals in a hospital-based pneumococcal surveillance system were evaluated. The MIC to penicillin or ampicillin was greater than or equal to 0.1 micrograms/ml for 274 (5%) isolates; 1 had an MIC of 4.0 micrograms/ml to penicillin. Seventeen (0.3%) were resistant to erythromycin (MIC, greater than or equal to 8 micrograms/ml), 157 (2.9%) were resistant to tetracycline (MIC, greater than or equal to 16 micrograms/ml), and 34 (0.6%) were resistant to sulfamethoxazole/trimethoprim (MIC, greater than or equal to 76 and 4 micrograms/ml). Isolates relatively resistant to penicillin represented 1.8% of isolates in 1979, 8% in 1982, and 3.6% in 1987. Sixty-five multiply resistant isolates were identified. Pneumococci from the southwestern United States (region 4) were more likely to be relatively resistant to penicillin. Using logistic regression analysis, serotypes 14 and 19A, isolates from region 4, and isolates from middle ear fluid were associated with penicillin resistance (P less than or equal to .008, chi 2. These data confirm that antimicrobial resistance among pneumococcal isolates remained at low levels in the United States through 1987.