Foregut duplication cysts are rare congenital anomalies of enteric origin that arise during early embryonic development. They are usually incidentally found on routine imaging studies. The diagnosis can usually be made by computed tomography (CT) and endoscopic ultrasound (EUS) appearance. On CT, cyst attenuation values usually measure 0+/-20 Hounsfield units (HU). Higher HU is possible with hemorrhage, proteinaceous material or septations. At EUS, characteristic location and anechoic as well as hypoechoic but not necessarily anechoic appearance may be suggestive of a foregut duplication cyst. EUS-guided fine needle aspiration (FNA) has been thought to provide a safe, minimally invasive approach to establish the diagnosis. The purpose of this report is to highlight the potential for infectious risk of EUS-FNA for these cysts, and to suggest CT and EUS features that can suggest this diagnosis without FNA. Three patients who underwent EUS-FNA for diagnosis of incidental mediastinal lesions developed cyst infection despite accepted techniques including prophylactic antibiotics. Combined CT and EUS appearance may be sufficient in making this diagnosis without FNA. IV antibiotics may not be completely protective against infectious complications of FNA of mediastinal duplication cysts.