An outbreak of serious infections due to gentamicin-resistant Klebsiella pneumoniae occurred in a neonatal intensive care unit in which the combination of gentamicin sulfate and ampicillin sodium had been used for standard initial therapy for suspected sepsis for nearly 11 years. After institution of control measures that included the substitution of cefotaxime sodium for gentamicin in the standard regimen, the outbreak promptly subsided. Nevertheless, a second outbreak of serious infections due to cefotaxime-resistant Enterobacter cloacae began ten weeks later. Sequential stool cultures from patients in the unit confirmed the disappearance of gentamicin-resistant K pneumoniae and the emergence of cefotaxime-resistant E cloacae after the change in antibiotic policy. These observations suggest that routine use of newer cephalosporins for therapy of suspected sepsis may lead to the emergence of drug-resistant microorganisms more rapidly than has occurred with the aminoglycosides.