We evaluated the delivery of ¹⁴C -cytosine arabinoside (AraC) to rat brain by: 1) intravenous (IV) bolus, by 2) intrathecal (IT) and 3) intraventricular (IVT) infusion, and by 4) convection-enhanced delivery (CED) into the caudate nucleus. Plasma and brain AraC metabolites were measured with HPLC, and distribution and concentration of ¹⁴C -AraC in brain sections were measured by quantitative autoradiography. After IV administration, the α and β plasma half-lives were 1.9 and 46.5 min, respectively. The blood-to-brain transfer constant of AraC was 2.5±1.4 μl g⁻¹ min⁻¹, compatible with high water solubility. After IT and IVT administration, tissue levels were high at the brain and ventricular surfaces, but declined exponentially into brain. After CED, maximum brain levels were up to 10,000 times higher than the IV group, and the distribution pattern was one of high ¹⁴C -AraC concentration in the convective component, with exponentially declining concentrations outside this region. The rate loss constant from brain was 0.002±0.0004 min⁻¹, suggesting that AraC was accumulating in brain cells. AraC was metabolized into uracil arabinoside within the brain. ¹⁴C -AraC was infused into 1 dog and distributed widely in the ipsilateral hemisphere. These studies suggest that delivery of AraC to brain parenchyma by the IV, IT or IVT routes will be subtherapeutic. Delivery by CED can achieve, and maintain, therapeutic levels of AraC in the brain, and should be further evaluated as a potential method of drug delivery.