Concentrations of pyrimidine nucleosides (with the possible exception of uridine) and oxypurines in mammalian plasma and cerebrospinal fluid (CSF) are maintained relatively constant by potent homeostatic mechanisms. To test the importance of the intact liver in maintaining homeostasis of pyrimidine nucleosides and oxypurines in plasma and CSF, we performed a greater than 90% or sham hepatectomy on New Zealand white rabbits. At 1, 6, 12, or 24 hours after real or sham hepatectomy, plasma and CSF nucleosides and oxypurines were measured by high-performance liquid chromatography. At all times after hepatectomy, the concentrations of the pyrimidine deoxyribonucleosides (deoxycytidine, deoxyuridine, and thymidine) were increased approximately threefold in plasma and CSF compared with sham-operated controls. Twenty-four hours after hepatectomy, the concentrations of uridine and cytidine in plasma were decreased by 70% and 50%, respectively, and in CSF by 50% and 40%, respectively, when compared with the concentrations in the sham-operated controls. Hypoxanthine concentrations in CSF were increased approximately twofold at 6, 12, and 24 hours after hepatectomy. These results suggest that liver function is essential for the maintenance of normal concentrations of pyrimidine nucleosides in plasma and CSF. That pyrimidine nucleoside concentrations are disrupted in plasma and CSF in this model of acute liver failure suggests that pools of pyrimidine nucleotides in some tissues (e.g., brain) may be altered by liver failure.