Purpose: To evaluate the role of positron emission tomography (PET)/computed tomography (CT) in the differentiation of normal thymus from mediastinal lymphoma and lymphoma recurrence in pediatric patients. Materials and Methods: The study was approved by the institutional review board, and informed consent was waived. The study was HIPAA compliant. Two hundred eighty-two fluorine 18 fluorodeoxyglucose PET/CT studies in 75 pediatric oncology patients were reviewed retrospectively. Patients were divided into four groups: anterior mediastinal lymphoma (group A, n = 16), anterior mediastinal lymphoma with subsequent recurrence (group B, n = 5), lymphoma outside the mediastinum (group C, n = 16), and other malignant tumors outside the thymus (group D, n = 38). Analyses included measurements of the maximum anteroposterior and transverse dimensions of the anterior mediastinal mass or thymus on axial CT images and measurements of maximum standardized uptake values of anterior mediastinal mass, thymus (SUV t), and bone marrow at the level of the fifth lumbar vertebra (SUV b) on PET images. Quantitative parameters were compared by using an analysis of variance test. Results: Mean prechemotherapy SUV t was 4.82 for group A, 8.45 for group B, 2.00 for group C, and 2.09 for group D. Mean postchemotherapy SUV t for group B was 4.74. Thymic rebound (mean SUV t, 2.89) was seen in 44% of patients at a mean interval of 10 months from the end of chemotherapy. The differences between prechemotherapy SUV t of mediastinal lymphoma and normal thymus and postchemotherapy SUV t of lymphoma recurrence and thymic rebound were highly significant (P<.001). Conclusion: SUV t is a sensitive predictor for differentiation of normal thymus or thymic rebound from mediastinal lymphoma. SUV t of 3.4 or higher is a strong predictor of mediastinal lymphoma.