Introduction: Selective decontamination of the digestive tract (SDD) in ICU patients is normally done using enteral antibiotics and intravenous cefotaxime, a third generation cephalosporin. On the introduction of SDD to our unit, we investigated if cefotaxime could be replaced by first generation cefazolin. Patients and methods: The study was a prospective cohort study of before-and-after design. All patients expected to be ventilated for more than 48 hours were included. In total 113 admissions were studied. In the first six months no SDD was given, in the next six months SDD was administered using intravenous cefazolin in the first four days and enteral polymyxin, tobramycin and amphotericin B (PTA) throughout ICU treatment. Results: On admission aerobic Gram negative bacilli (AGNB), excluding P aeruginosa, were cefazolin-resistant in 31 patients and cefotaxime-resistant in two patients, p<0.001, RR 0.06 (95% CI 0.02-0.26). SDD patients had significantly less AGNB and fungi in late cultures. Antimicrobial resistance was reduced in the SDD group. S aureus or enterococcal carriage was not different. Conclusions: SDD with enteral PTA combined with intravenous cefazolin during the first four days of ventilation reduces AGNB carriage, without antimicrobial resistance emerging. Thirty-one percent of patients however were admitted while carrying cefazolin-resistant AGNB. We conclude that cefazolin is not appropriate as the parenteral component in SDD. Copyright © 2008, Nederlandse Vereniging voor Intensive Care. All Rights Reserved.