Objective: Diagnosis of transplant rejection requires endomyocardial biopsy and entails risks. Here, we describe a new 19F MRI approach for detection of organ rejection by noninvasive visualization of the macrophage host response. We employed biochemically inert emulsified perfluorocarbons (PFCs), which were reported to be preferentially phagocytized by monocytes and macrophages. Methods: Isografts from C57BL/6 and allografts from C57BL/10A mice were heterotopically transplanted into C57BL/6 recipients followed by intravenous injection of a 10% emulsion of perfluoro-15-crown-5 ether at various times after surgery. In this model, the transplanted heart undergoes predictable progressive rejection, leading to graft failure after 2-3 weeks. Mice were imaged at 9.4 T using a Bruker DRX NMR spectrometer. Results: To exclude that inflammatory processes by the surgical intervention may mask the immune reaction induced by rejection, we first compared genetically identical isografts with allografts. 1H images showed a similar position and anatomy of the graft in the abdomen for both cases. However, corresponding 19F signals were only observed in the allograft. 1H/19F MRI enabled us to detect the initial immune response not later than 3 days after surgery, when conventional parameters did not reveil any signs of rejection. In allografts, the observed 19F signal strongly increased with time correlating with the extent of rejection. In separate experiments, rapamycin was used to demonstrate the ability of 19F MRI to monitor immunosuppressive therapy. Histologic analysis of the number of CD11b-positive cells within the myocardium of the graft confirmed that 19F signal intensity correlates with the quantity of infiltrating immune cells. Conclusions: PFCs can serve as positive contrast agent for the early detection of transplant rejection by 19F MRI with high spatial resolution and an excellent degree of specificity due to lack of any 19F background.