Myeloid sarcoma is a tumor formed by extramedullary accumulation of myeloblasts or immature myeloid cells. These tumors can develop in lymphoid organs, bone, skin, soft tissue, and other organs, and may precede or occur concurrently with acute myeloid leukemia. This is a case of a 42-year-old man who presented with a 2-week history of cough and shortness of breath on exertion. A computed tomography (CT) scan showed a large mediastinal mass and pericardial effusion. An F-18 fluorodeoxyglucose positron emission tomography-CT scan showed intense fluorodeoxyglucose (FDG) uptake in the mediastinal mass with invasion of the parietal pericardium. Biopsy of the mediastinal mass and pericardium revealed myeloid sarcoma. The pericardial effusion was drained and the patient was treated with high-dose cytosine arabinoside (HiDAC) chemotherapy. A follow-up positron emission tomography-CT was done 2 months after the last cycle, showing poor response to therapy and significant progression of disease with invasion through the anterior chest wall. Myeloid sarcoma can be added to the differential diagnosis of F-18 FDG avid anterior mediastinal masses, as well as F-18 FDG uptake in the pericardium.