Background— Macrophages predominate among the inflammatory cells in rejecting allografts. These innate immune cells, in addition to allospecific T cells, can damage cardiomyocytes directly. Methods and Results— We explored whether sensitive positron emission tomography–computed tomography (PET-CT) imaging of macrophages-avid nanoparticles detects rejection of heart allografts in mice. In addition, we used the imaging method to follow the immunomodulatory impact of angiotensin-converting enzyme inhibitor therapy on myeloid cells in allografts. Dextran nanoparticles were derivatized with the PET isotope copper-64 and imaged 7 days after transplantation. C57BL/6 recipients of BALB/c allografts displayed robust positron emission tomography signal (standard uptake value allograft, 2.8±0.3; isograft control, 1.7±0.2; P <0.05). Autoradiography and scintillation counting confirmed the in vivo findings. We then imaged the effects of angiotensin-converting enzyme inhibitor (5 mg/kg enalapril). Angiotensin-converting enzyme inhibitor significantly decreased nanoparticle signal ( P <0.05). Histology and flow cytometry showed a reduced number of myeloid cells in the graft, blood, and lymph nodes and diminished antigen presentation ( P <0.05 versus untreated allografts). Angiotensin-converting enzyme inhibitor also significantly prolonged allograft survival (12 versus 7 days; P <0.0001). Conclusions— Nanoparticle macrophage PET-CT detects heart transplant rejection and predicts organ survival by reporting on myeloid cells.