There is little information regarding the pharmacology of 5-fluorouracil (5-FUra) in the central nervous system (CNS), despite its role in the treatment of diseases with CNS metastases and recent reports of neurotoxicity. In this study, the plasma and cerebrospinal fluid (CSF) pharmacokinetics of 5-FUra were examined in a primate model. Following a bolus dose, the area under the concentration versus time curves for 5-FUra in CSF was 48% of the plasma area under the concentration versus time curves. For continuous infusion of 5-FUra, the area under the concentration versus time curves ratio for CSF:plasma was 20 or 11%, depending upon the infusion rate. The mechanism for variations in CSF exposure based upon the pattern of plasma delivery is consistent with local metabolism of 5-FUra in the CNS. These findings should be considered in the evaluation of delivery schedules which are intended to maximize drug delivery to the CNS and/or minimize neurotoxicity.