Combined 18F-fluoro-deoxyglucose ([18F]FDG) positron emission tomography and computed tomography ([18F]FDG-PET/CT) is increasingly used for the diagnostic and therapeutic management of hematologic and non-hematologic malignancies. Here, we describe a unique case of a patient presenting with very severe aplastic anemia and a mediastinal mass showing disseminated hypermetabolic lesions of the bones after receiving granulocyte colony-stimulating factor (G-CSF), highly suspicious for disseminated metastatic lesions. A 71-year-old patient presented with a 3 week history of dyspnea and fatigue. Blood tests showed severe pancytopenia and iliac crest bone marrow biopsy revealed an extensively hypoplastic bone marrow. Diagnostic work-up by histology, conventional cytogenetics and flow cytometry confirmed the diagnosis of very severe aplastic anemia. Besides blood transfusions, the patient was treated with G-CSF. Furthermore, computed tomography revealed a suspect mass in the anterior mediastinum, presenting with moderate glucose metabolism in the subsequent [18F]FDG-PET/CT scan. In addition, multiple disseminated and highly metabolic bone lesions of primarily the ribs were detected, suspicious of malignant bone infiltration. Since physiologic bone marrow activation by G-CSF-stimulation could not be ruled out, G-CSF therapy was interrupted to repeat the PET/CT scan 10 days later. On the second [18F]FDG-PET/CT the moderately hypermetabolic mediastinal mass persisted. However, the initially FDG-avid bone lesions almost completely resolved, rendering the diagnosis of G-CSF-induced bone marrow hypermetabolism very likely without the need for further invasive diagnostic procedures. The mediastinal mass was thereafter histologically verified as thymoma. Interpretation of [18F]FDG-PET/CT in patients with aplastic anemia may be complicated by the frequent therapeutic use of G-CSF. With G-CSF, islets of residual bone marrow activity can be visualized on [18F]FDG-PET/CT images that might be misinterpreted as malignant bone infiltration. Repeating PET/CT scan after G-CSF discontinuation can prevent unnecessary invasive diagnostic procedures in these patients.