Rationale: Myeloid cell content in atherosclerotic plaques associates with rupture and thrombosis. Thus, imaging of lesional monocytes and macrophages could serve as a biomarker of disease progression and therapeutic intervention. Objective: To noninvasively assess plaque inflammation with dextran nanoparticle (DNP)-facilitated hybrid positron emission tomography/magnetic resonance imaging (PET/MRI). Methods and Results: Using clinically approved building blocks, we systematically developed 13-nm polymeric nanoparticles consisting of cross-linked short chain dextrans, which were modified with desferoxamine for zirconium-89 radiolabeling ( ⁸⁹ Zr-DNP) and a near-infrared fluorochrome (VT680) for microscopic and cellular validation. Flow cytometry of cells isolated from excised aortas showed DNP uptake predominantly in monocytes and macrophages (76.7%) and lower signal originating from other leukocytes, such as neutrophils and lymphocytes (11.8% and 0.7%, P <0.05 versus monocytes and macrophages). DNP colocalized with the myeloid cell marker CD11b on immunohistochemistry. PET/MRI revealed high uptake of ⁸⁹ Zr-DNP in the aortic root of apolipoprotein E knock out (ApoE ^−/− ) mice (standard uptake value, ApoE ^−/− mice versus wild-type controls, 1.9±0.28 versus 1.3±0.03; P <0.05), corroborated by ex vivo scintillation counting and autoradiography. Therapeutic silencing of the monocyte-recruiting receptor C-C chemokine receptor type 2 with short-interfering RNA decreased ⁸⁹ Zr-DNP plaque signal ( P <0.05) and inflammatory gene expression ( P <0.05). Conclusions: Hybrid PET/MRI with a 13-nm DNP enables noninvasive assessment of inflammation in experimental atherosclerotic plaques and reports on therapeutic efficacy of anti-inflammatory therapy.