OBJECTIVE Infection represents the most common serious complication of shunt surgery, and typically its incidence ranges between 5 and 15%, despite the use of systemic antibiotic agents. Because systemic antibiotic medications generally penetrate the cerebrospinal fluid (CSF) poorly, the authors investigated, in a controlled study, whether the addition of intraventricular antibiotic treatment decreases the incidence of perioperative infection in adult patients. METHODS Data pertaining to all CSF shunt procedures conducted at the authors' institution during an 11-year period were reviewed. Perioperative infection was defined as culture-positive CSF and the clinical presence of infection-related symptoms occurring within 90 days of surgery. All patients underwent intraoperative systemic antistaphylococcal antibiotic therapy. Before May 16, 1999, the senior author (R.H.S.) also administered 4 mg of gentamicin intraventricularly at surgery (Group I); thereafter, 10 mg of vancomycin was additionally administered (Group II). Other neurosurgeons at this institution did not use intraventricular antibiotic therapy, and their patients served as additional controls in identical time periods (Groups III and IV). A total of 802 shunt procedures were performed in 534 patients. Control infection rates were 5.4% (eight of 147) in Group I; 6.2% (nine of 145) in Group III; and 6.7% (18 of 267) in Group IV. With the combination of systemic antibiotic and intraventricular gentamicin and vancomycin (Group II), the infection rate fell significantly to 0.4% (one of 243). No complications were noted in association with intraventricular antibiotic administration. CONCLUSIONS The combination of intraventricular gentamicin and vancomycin with systemic antibiotic therapy significantly decreased the incidence of perioperative shunt infection. It is presumed that intraventricular antibiotic therapy extends prophylactic antibiotic coverage into the CSF and prevents bacterial seeding.