The objective of the present study was to evaluate systemic and local effects of cefepime alone and/or in combination with vancomycin in the prevention of experimentally implanted Dacron and ePTFE vascular grafts infected with Staphylococcus aureus in rat. Ninety healthy adult male Wistar rats were divided into two groups of 45 animals each. Then, each group was subdivided into nine subgroups of 5 animals each. Following anesthesia, in each rat one cm2, sterile Dacron or ePTFE graft was implanted aseptically into dorso-lumbar subcutaneous pocket. The grafts were infected by inoculation of one ml of (5 × 107 CFU/ml) Staphylococcus aureus suspension. The rats received vancomycin or cefepime locally, intraperitoneally, or in combinations. The grafts were removed seven days after implantation and evaluated by quantitative culture. Combinations of cefepime with vancomycin resulted in enhanced efficiency of antibiotics in bacterial growth inhibition. Local vancomycin was more effective than local cefepime in the reduction of graft contamination. A combination of intraperitoneal vancomycin, as well as local cefepime, was more effective than a combination of intraperitoneal cefepime as well as intraperitoneal vancomycin in the Dacron group. Local vancomycin-intraperitoneal cefepime combination could be suggested to prevent Dacron and ePTFE vascular graft infected with Staphylococcus aureus. Local treatment alone, vancomycin for Dacron graft and cefepime for ePTFE graft, and intraperitoneal treatment alone, vancomycin for ePTFE graft, could also be suggested.