X-ray computed tomography (CT) is one of the most widely used imaging procedures in diagnostic medicine due to its many advantages that include cost effectiveness, deep tissue penetration, and high resolution. [1][2][3][4][5] Currently, small iodinated molecules are routinely used for in vivo contrast enhancement in the clinical setting. Iodinated molecules can effectively absorb X-rays but suffer from short circulation lifetime and potential renal toxicity.[6] Another notable disadvantage is the relatively low K-edge of iodine (33 keV). X-rays that are optimized for this K-edge have a higher potential for damaging tissues. Nanoparticulate CT contrast agents that comprise high atomic number (high-Z) metal elements (mainly focused on gold, platinum, bismuth, and tantalum) have been proved to be a powerful tool to address these issues. [7][8][9][10][11][12][13] These nanoparticulate CT contrast agents have exhibited good imaging effects, acceptable safety profiles, and long circulation half times in vivo. Nevertheless, these metal elements, in principle, would not display prominent superiority in contrast efficacy with respect to clinical iodinated agents under normal operating conditions (120 kVp), because their attenuation characteristics are mismatched with the X-ray photon energy used in clinical CT.[14a] Moreover, administration of a large amount of contrast agent is often required in CT imaging, and the very low abundance of these elements in the earths crust is most likely to result in huge cost issues. [14b] Compared to the currently available Au-, Pt-, Bi-, and Tabased nanomaterials, Yb-based nanostructures hold great promise as CT contrast agents. The benefits of Yb in nanomaterials are as follows: 1) its K-edge energy (61 keV) is located just within the higher-energy region of the X-ray spectrum used in clinical CT, hence ensuring both higher intrinsic contrast and lower radiation exposure to the patients; [15a,b] 2) low toxicity when encapsulated in the stable nanoparticle; [15c] 3) the highest abundance in the earths crust among these metals, [14b] and thus it has a potential for industrial production; and 4) Yb is a well-known component of upconversion luminescence nanocrystals, which provides a particularly useful platform for the design of multimodal imaging nanoprobes without additional modification of functionalities. Nevertheless, to our knowledge, Yb-based nanoparticulate CT contrast agents have remained unexplored until now.Herein, we describe the first example of Yb-based nanoparticulate CT contrast agents. For these nanoparticles, not only the surface modification but also the control over the size and morphology can be easily achieved. More significantly, owing to the attenuation characteristics of Yb-based nanoparticles, which are matched with the X-ray photon energy used in clinical applications, they can offer a much higher contrast efficacy compared to clinical iodinated agents at 120 kVp. Together with long circulation time and low toxicity, these nanoparticles can act as a high-p...