In an analysis of 4766 consecutive strains of Streptococcus pneumoniae isolated from cultures of blood from 1979 to 1986 and of 1157 isolates from cerebrospinal fluid (CSF), resistance was found in 380 (8%) of blood and 107 (9.2%) of CSF isolates to one or more of the following antibiotics: penicillin, tetracycline, erythromycin, clindamycin, rifampin, and chloramphenicol. Resistance increased from 3.8% to 14.1% among isolates from blood and from 6.8% to 14.1% among CSF isolates during this period. Comparing 1979-1982 with 1983-1986, we found that significant increases (P less than .01) have occurred in penicillin resistance alone, rifampin resistance alone, and in strains showing multiple resistance. Resistance was found in 15 different serogroups and/or serotypes, although 92.2% of resistant strains belonged to serogroups 6 or 19 or to serotype 14. Of the serogrouped or serotyped strains, 97.4% are represented in the 23-valent vaccine by a vaccine or vaccine-related strain.