Convection-enhanced delivery of macromolecules in the brain involves using pressure gradients during interstitial infusion to generate bulk flow through the brain interstitium, thereby enhancing the distribution of large and small molecules. This method was tested with ¹¹¹In-labeled transferrin (¹¹¹In-Tf) and [¹⁴C] sucrose, which showed increased distribution and homogeneity in the brain after infusion. The volume of distribution (Vd) containing ≥1% of the infusion solution concentration increased linearly with the infusion volume (Vi), indicating that convection significantly enhances drug delivery. The blood-brain barrier limits drug penetration into the central nervous system (CNS), but direct administration into the brain parenchyma or cerebrospinal fluid (CSF) can bypass this barrier. However, diffusion alone is insufficient for effective drug delivery, especially for large molecules. Convection, generated by maintaining a pressure gradient during infusion, can overcome this limitation by facilitating bulk flow through the brain interstitium. In this study, convection was used to deliver ¹¹¹In-Tf and [¹⁴C] sucrose into the brain of anesthetized cats. The results showed that convection significantly increased the distribution of these molecules, with ¹¹¹In-Tf penetrating gray matter and [¹⁴C] sucrose distributing more rapidly into gray matter. The Vd for both molecules increased over time, indicating that convection enhances drug delivery beyond what is possible with simple diffusion. The study also demonstrated that convection can achieve much higher drug concentrations in the brain compared to systemic levels. This method has the potential to overcome the limitations of drug diffusion through the brain interstitium, making it a promising approach for delivering drugs to the CNS, including for the treatment of neurodegenerative disorders, CNS tumors, and inborn errors of metabolism. The technique was well tolerated, with no significant hemodynamic instability or long-term neurological effects observed.Convection-enhanced delivery of macromolecules in the brain involves using pressure gradients during interstitial infusion to generate bulk flow through the brain interstitium, thereby enhancing the distribution of large and small molecules. This method was tested with ¹¹¹In-labeled transferrin (¹¹¹In-Tf) and [¹⁴C] sucrose, which showed increased distribution and homogeneity in the brain after infusion. The volume of distribution (Vd) containing ≥1% of the infusion solution concentration increased linearly with the infusion volume (Vi), indicating that convection significantly enhances drug delivery. The blood-brain barrier limits drug penetration into the central nervous system (CNS), but direct administration into the brain parenchyma or cerebrospinal fluid (CSF) can bypass this barrier. However, diffusion alone is insufficient for effective drug delivery, especially for large molecules. Convection, generated by maintaining a pressure gradient during infusion, can overcome this limitation by facilitating bulk flow through the brain interstitium. In this study, convection was used to deliver ¹¹¹In-Tf and [¹⁴C] sucrose into the brain of anesthetized cats. The results showed that convection significantly increased the distribution of these molecules, with ¹¹¹In-Tf penetrating gray matter and [¹⁴C] sucrose distributing more rapidly into gray matter. The Vd for both molecules increased over time, indicating that convection enhances drug delivery beyond what is possible with simple diffusion. The study also demonstrated that convection can achieve much higher drug concentrations in the brain compared to systemic levels. This method has the potential to overcome the limitations of drug diffusion through the brain interstitium, making it a promising approach for delivering drugs to the CNS, including for the treatment of neurodegenerative disorders, CNS tumors, and inborn errors of metabolism. The technique was well tolerated, with no significant hemodynamic instability or long-term neurological effects observed.