Abstract Purpose To determine local doxorubicin levels surrounding radiopaque drug-eluting beads (DEBs) in normal swine liver and kidney following transcatheter arterial chemoembolization. The influence of bead size (70–150 μm or 100–300 μm) was compared with regard to tissue penetration and spatial distribution of the bead, as well as eventual drug coverage (ie, amount of tissue exposed to drug). Materials and Methods Radiopaque DEBs were synthesized by suspension polymerization followed by incorporation of iodized oil and doxorubicin. Chemoembolization of swine liver and kidney was performed under fluoroscopic guidance. Three-dimensional tissue penetration of “imageable” DEBs was investigated ex vivo with micro–computed tomography (microCT). Drug penetration from the bead surface and drug coverage was evaluated with epifluorescence microscopy, and cellular localization of doxorubicin was evaluated with confocal microscopy. Necrosis was evaluated with hematoxylin and eosin staining. Results MicroCT demonstrated that 70–150-μm DEBs were present in more distal arteries and located in a more frequent and homogeneous spatial distribution. Tissue penetration of doxorubicin from the bead appeared similar (∼300 μm) for both DEBs, with a maximum tissue drug concentration at 1 hour coinciding with nuclear localization of doxorubicin. The greater spatial frequency of the 70–150-μm DEBs resulted in approximately twofold improved drug coverage in kidney. Cellular death is predominantly observed around the DEBs beginning at 8 hours, but increased at 24 and 168 hours. Conclusions Smaller DEBs penetrated further into targeted tissue (ie, macroscopic) with a higher spatial density, resulting in greater and more uniform drug coverage (ie, microscopic) in swine.