OBJECTIVE: To compare cefotaxime (CTX) to amoxicillin (AMO) (usually considered the definitive therapy for penicillin-susceptible Streptococcus pneumoniae infections) in an immunocompromised mouse pneumonia model. METHODS: Three S. pneumoniae clinical isolates were used: two serotype 19 strains, a penicillin-susceptible (Ps) strain (penicillin MIC=0.03 microg/mL) and a highly penicillin-resistant (Pr) strain (penicillin MIC=4 microg/mL), and one serotype 23F strain, a penicillin---cephalosporin-resistant (CFTR) strain (CTX MIC=4 microg/mL). RESULTS: CTX activity in this mouse model of pneumonia induced by the highly penicillin-resistant strain of S. pneumoniae was lower than expected from its low MIC against this organism. Furthermore, AMO had greater efficacy than CTX against a CFTR S. pneumoniae strain. CONCLUSION: Our data suggest that there is no major difference in the in vivo efficacy of the two agents, cefotaxime and amoxicillin, against penicillin-resistant and penicillin---cephalosporin-resistant S. pneumoniae.