Thirty-eight isolates of penicillin-intermediate and 28 isolates of penicillin-resistant Streptocococcus pneumoniae obtained from pediatric patients were tested against cefotaxime, ceftriaxone, cefuroxime, and ceftizoxime by microbroth dilution to determine minimum inhibitory concentrations (MICs). All penicillin-intermediate isolates were susceptible to ceftriaxone and cefotaxime, and the 90% MIC (MIC90) for these drugs (0.5 μg/mL) was 2 dilutions less than those of cefuroxime and ceftizoxime (2 μg/mL). Of the penicillin-intermediate isolates, 71% were susceptible to cefuroxime. All drugs were significantly less active against penicillin-resistant strains with only 9 (32%), 8 (29%), and 0 (0%) of these strains susceptible to ceftriaxone, cefotaxime, and cefuroxime, respectively. For penicillin-resistant strains, MIC90 was 4 μg/mL for ceftriaxone, 8 μg/mL for cefotaxime, 32 μg/mL for cefuroxime, and 64 μg/mL for ceftizoxime. This in vitro study demonstrated that ceftriaxone and cefotaxime are more active than cefuroxime and ceftizoxime against penicillin-intermediate and penicillin resistant S pneumoniae isolated from children.