A prospective double-blind placebo-controlled study was performed to evaluate the efficacy of cloxacillin for the prevention of infections after craniotomy. 310 patients were admitted to the study. 39 died within 90 days after craniotomy without an infection, 20 and 19 of them belonging to the cloxacillin and placebo groups, respectively. In the cloxacillin group 6 neurosurgical infections occurred after 183 operations (3.3%) in 156 patients (3.9%), and in the placebo group 20 after 195 operations (10.3%) in 154 patients (13%). These differences between the 2 groups are statistically significant (p less than 0.01 and p less than 0.05 for patients and operations, respectively). For a craniotomy subgroup, there was no significant difference in infection rate between the cloxacillin and placebo groups. We conclude that cloxacillin significantly reduces the rate of infection after craniotomy, and recommend administration of this antibiotic for prophylaxis in patients undergoing this operation.