The objective of this study was to determine if perioperative antimicrobial prophylaxis decreases the incidence of subsequent shunt infection in patients who require placement of internal CSF shunts. Data sources included a computerized search of two biomedical data bases, contact with colleagues, and a review of abstracts of meetings and of references of identified trials and reviews. Studies were chosen for detailed review if they involved human subjects who underwent CSF shunt placement, with random allocation of patients to groups receiving perioperative systemic antimicrobial agents or to a control group and an outcome measure of subsequent shunt infection. Twelve (32%) of 37 studies met selection criteria and were included. Features of trial design were extracted and trial quality was evaluated with use of a predetermined protocol by three independent investigators who were blinded to titles, authors, and institutions. Individually, only one of 12 trials achieved statistical significance favoring prophylaxis; in the aggregate, the use of prophylactic antibiotics was associated with a significant reduction in subsequent CSF shunt infection (Mantel-Haenszel weighted risk ratio: 0.52; 95% confidence interval: 0.37, 0.73; P = .0002; approximate risk reduction: 50%). This systematic overview of 12 trials of 1,359 randomized patients demonstrates that perioperative use of antimicrobial agents in CSF shunt placement significantly reduces the risk of subsequent infection.