To compare efficacy, tolerability, and cost of antibiotic prophylaxis with teicoplanin and cefazolin in clean prosthetic vascular surgery, a randomized, prospective, double-blind study was performed at the Vascular Surgery Unit of a tertiary-care university hospital. Two-hundred thirty-eight consecutive patients undergoing elective, clean, abdominal or lower-limb prosthetic vascular surgery were allocated to receive a single intravenous dose of teicoplanin (400 mg) or cefazolin (2 g) at the induction of anesthesia. Surgical-site infections occurred in 5.9% of teicoplanin recipients (4.2% wound infection, 1.7% graft infection) and 1.7% of cefazolin recipients (1.7% wound infection, 0% graft infection) (P=0.195). Other postoperative infections occurred in 10% of teicoplanin recipients (pneumonia 7%, urinary tract infection 3%) and 12% of cefazolin recipients (pneumonia 7%, urinary tract infection 2.5%, bloodstream infections 2.5%). Overall mortality rate was 3.4% in teicoplanin recipients (4 patients) and 2.5% in cefazolin recipients (3 patients). Infective deaths occurred in one patient for each group. The two prophylactic regimens were well tolerated. Cost savings of US $52,510 favoring cefazolin were related to the lower acquisition cost (US $1034 vs US $4740) and to the shorter duration of the hospital stay (1762 days vs 1928 days). Cefazolin can still be regarded as the drug of choice for prophylaxis in clean vascular surgery.