A randomized, double-blind, placebo-controlled trial of perioperative rifampin-trimethoprim was undertaken at the Hospital for Sick Children from March 1984 to October 1987, in which 243 patients undergoing 300 cerebrospinal fluid (CSF) shunting procedures were randomized into groups including treatment with rifampin/trimethoprim and placebo, and then followed for a minimum of 2 years. Patients were stratified prior to randomization into those with and those without meningomyeloceles having first insertions of their shunts, and those having revisions. Patients could be entered into the study more than once, but always received the same treatment regimen once allocation had taken place. Among the patients receiving antibiotics there was an infection rate of 12%, versus 19% among patients receiving placebo. Among the surgical procedures, the rates were 9% and 15%, respectively. Because these rates of infection were a substantial increase over the rate of 7.5% overall for the few years prior to implementation of the study, and well over any acceptable rate of infection, the study, was stopped before statistical significance was reached. However, had the study continued, and the proportions of patients becoming infected remained constant, we would have been able to achieve a statistically significant difference in rates of infection, and therefore demonstrate a benefit of rifampin/trimethoprim as prophylaxis against shunt infection. Methodological problems encountered in this and other studies of prevention of CSF shunt infection will be discussed. © 1992 Springer-Verlag.