Ceftizoxime and cefotaxime demonstrate very similar activities in vitro against a broad range of bacteria. To reduce costs, our hospital pharmacy implemented an automatic substitution policy whereby ceftizoxime was dispensed and administered whenever cefotaxime was ordered. This policy was modified when penicillin-resistant Streptococcus pneumoniae isolates were found to be markedly less susceptible to ceftizoxime than to cefotaxime, of concern considering the prevalence and virulence of this pathogen. We compared clinical findings among 179 adult patients treated with ceftizoxime for any indication during the substitution months with 200 patients treated with cefotaxime during the previous year. The ceftizoxime group had a shorter mean length of stay, which paralleled a hospital-wide trend toward more efficient discharge planning. After adjusting for this trend, we observed no significant difference in duration of study drug, number of other intravenous antibiotics, likelihood of receiving additional antibiotics after study drug completion, or patient survival. Fortuitously, no penicillin-resistant pneumococcal infections were documented in ceftizoxime-treated patients. This study suggests that cefotaxime and ceftizoxime are comparable. The choice of one versus the other may be dictated by price, provided ceftizoxime is not used for proven or suspected penicillin-resistant pneumococcal infections.