Purpose: To study the value of 2-deoxy-2-[18F]fluoro-D-glucose([18F]FDG) positron emission tomography/computed tomography(PET/CT) and [18F]FDG positron emission tomography/magnetic resonance imaging (PET/MRI) in assessing immunocompromisedpatients with suspected malignancy or infection. Methods: [18F]FDG-PET/CT and [18F]FDG-PET/MRI examinations of patients who were immunocompromised after receivinglung, heart, pancreas, kidney, liver, or combined kidney-liver transplants were analyzed in this retrospective study. Patientsunderwent whole-body hybrid-imaging because of clinical signs of malignancy and/or infection. Findings were assessed bymolecular features ([18F]FDG-uptake) and morphological changes. The final diagnosis, which was arrived at after review ofclinical, laboratory, and histopathologic analyses and follow-up imaging studies, served as the reference standard. Results: Altogether, (i) 28 contrast-enhanced [18F]FDG-PET/CT scans (CE-PET/CT), (ii) 33 non-contrast [18F]FDG-PET/CTscans (NC-PET/CT), and (iii) 18 [18F]FDG-PET/MRI scans were included. Additionally, 12/62 patients underwent follow-upPET imaging to rule out vital tumor ormetabolic active inflammatory processes. CE-PET/CT exhibited 94.4%sensitivity, 80.0%specificity, 89.5% positive predictive value (PPV), 88.9% negative predictive value (NPV), and 89.3% accuracy with regard tothe reference standard. NC-PET/CT exhibited 91.3% sensitivity, 80.0% specificity, 91.3% PPV, 80.0% NPV, and 87.9% accuracy. PET/MRI exhibited 88.6% sensitivity, 99.2% specificity, 99.6% PPV, 81.3% NPV, and 94.4% accuracy. ExactMcNemar statistical test (one-sided) showed significant difference between the CT-/MR-component alone and the integratedPET/CT and PET/MRI for diagnosis of malignancy or infection (p value < 0.001). Radiation exposure was 4- to 7-fold higherwith PET/CT than with PET/MRI. Conclusion For immunocompromised patients with clinically unresolved symptoms, to rule out vital tumor manifestations ormetabolic active inflammation, [18F]FDG-PET/MRI, CE-[18F]FDG-PET/CT, and NC-[18F]FDG-PET/CT exhibit excellent performancein diagnosing malignancy or infection. The main strength of PET/MRI is its considerably lower level of radiationexposure than that associated with PET/CT.