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RATIONALE AND OBJECTIVES To show that water and iodine two-material decomposition images from dual-layer dual-energy spectral X-ray computed tomography (DECT) can be used to separate intravascular iodine contrast from simultaneously administered oral tantalum, tungsten, or rhenium contrast in an animal model. MATERIALS AND METHODS In this Institutional Animal Care and Use Committee approved study, four female Fischer rats were given simultaneous intravenous and oral X-ray computed tomography contrast. Intravenous iodine contrast was administered via tail vein injection. Oral barium, tantalum, tungsten, or rhenium contrast was administered via gavage. The animals were imaged on a dual-layer DECT system at 120 kVp. Water and iodine two-material decomposition images (water equivalent and iodine equivalent images) were used for qualitative analysis. Computer simulations were performed using a customized DECT simulator to better understand why certain high-Z elements disappear in the iodine equivalent images and what is the theoretical range of elements with this property. RESULTS The iodine and barium contrast appeared only in the iodine equivalent images and could not be differentiated from each other. However, the tantalum, tungsten, and rhenium contrast only appeared in the water equivalent images. This allowed iodine contrast in the bowel wall to be easily segmented from tantalum, tungsten, and rhenium contrast in the bowel lumen. Simulations confirmed that certain high-Z elements will have pixel values of ≤0mg iodine/mL in the iodine equivalent images due to a K-edge effect associated with DECT systems. CONCLUSIONS Dual-layer DECT can separate iodine from certain high-Z elements using water equivalent and iodine equivalent images with an increased element range compared to other DECT systems. This K-edge effect could promote the development and approval of new high-Z contrast agents for DECT.