A prospective, randomized, blinded study was performed to determine whether prophylactic antibiotics would reduce the incidence of infection in peripheral vascular surgery and whether the route of antibiotic administration was important. Patients undergoing a vascular procedure with a groin incision were allocated to one of four groups with respect to prophylactic antibiotics. Group I received no antibiotic. Group II had topical cephradine instilled in their incisions prior to closure. Group III received a 24-hour perioperative course of intravenous cephradine, and Group IV received both topical and intravenous cephradine. Groin and abdominal incisional infections were significantly reduced (p < 0.01) among patients who received prophylactic antibiotics by either the topical, systemic, or combined routes of administration. No significant differences were noted among the three antibiotic groups. Profundoplasty, femoral embolectomy, and femoral aneurysm repair were each associated with an increased incidence of infection (p < 0.01). Other risk factors were only important in patients not receiving antibiotics. Either intraoperative topical antibiotics or perioperative systemic antibiotics prevent infection in peripheral vascular surgery, but antibiotic administration by both routes is unnecessary.