An animal model was developed for studying the pharmacokinetics of antibiotics administered intraventricularly in hydrocephalus. Obstructive hydrocephalus was consistently produced in craniectomized adult rats by injecting kaolin into the cisterna magna. After induction of hydrocephalus, vancomycin was injected into the right lateral ventricle of each rat. Bilateral ventricular cerebrospinal fluid (CSF) and brain parenchymal samples were obtained at 0.5, 1, 2, 4, 8, and 12 hours and the concentration of vancomycin in these samples was determined. Brain tissue was also analyzed histologically. The results show: (a) vancomycin is rapidly distributed within the CSF, including the contralateral ventricle, within 30 minutes; (b) vancomycin concentrations were nearly identical in both ventricles at all time points; (c) mean peak CSF vancomycin concentrations occurred at 2 hours and were 23.8 and 21.3 μg/ml for the left and right lateral ventricles, respectively; (d) elimination from CSF was slow (T1/2β = 2.22 hours, T1/2γ = 19.65 hours); (e) no vancomycin was detected (≤2 μg/g) in the samples of periventricular white matter; (f) histological changes observed were consistent with untreated obstructive hydrocephalus and did not seem to be related to vancomycin treatment. The clinical significance of these results and the usefulness of the experimental model are discussed.