Recent experimental studies have shown convective-enhanced delivery (CED) to be useful for transporting macromolecular therapeutic agents over large tissue volumes in the central nervous system (CNS). There are limited tools currently available for predicting tissue distributions in the brain. We have developed a voxelized modeling methodology in which CNS tissues are modeled as porous media, and transport properties and anatomical boundaries are determined semi-automatically on a voxel-by-voxel basis using diffusion tensor imaging (DTI). By using this methodology, 3D extracellular transport models of the rat brain were developed. Macromolecular tracer distributions following CED in two different infusion sites (corpus callosum and hippocampus) were predicted. Sensitivity of models to changes in infusion parameters, transport properties, and modeling parameters was determined. Predicted tracer distributions were most sensitive to changes in segmentation threshold, DTI resolution, tissue porosity, and infusion site. This DTI-based voxelized modeling methodology provides a potentially rapid means of estimating CED transport.