Antimicrobial susceptibilities were performed at the Centers for Disease Control on 3400 Streptococcus pneumoniae isolates that were collected during a national survey of serotype-distribution of pneumococci found in normally sterile body fluids. The results showed 126 isolates (3.7%) to be relatively resistant to penicillin (RPR). The RPR strains were tested for susceptibility to cefuroxime, ceftriaxone, cefotaxime, cefamandole, cefaclor, ceftazidime, and moxalactam. These newer generation cephalosporin drugs were tested either because of their ability to penetrate into the cerebrospinal fluid (CSF) or for their activity against pneumococci. Three hundred ninety-one pneumococci were tested with 179 resistant to at least one antimicrobial. The RPR strains were not categorically resistant to the cephalosporins but were fourfold more resistant to them than were the penicillin-susceptible strains. The three most effective antimicrobials in the study for RPR were cefuroxime, cefotaxime, and ceftriaxone [corrected]. Each gave MICs that were attainable in CSF for RPR. Fifty percent of the RPR were inhibited by 0.06 mg/ml and 90% by 0.25 micrograms/ml of these antimicrobials. The least effective were cefaclor, moxalactam, and ceftazidime.