Background: Plasmoblastic lymphoma is a rare and aggressive subtype of diffuse large B cell lymphoma, which occurs usually in the jaw of immunocompromised subjects. Case presentation: We describe the occurrence of plasmoblastic lymphoma in the mediastinum and chest wall skin of an human immunodeficiency virus-negative 63-year-old Caucasian man who had had polycytemia vera 7 years before. At admission, the patient showed a superior vena cava syndrome, with persistent dyspnoea, cough, and distension of the jugular veins. Imaging findings showed a 9.7 × 8 × 5.7 cm mediastinal mass. A chest wall neoformation biopsy and ultrasound-guided fine-needle aspiration biopsy of the mediastinal mass allowed diagnosis of plasmoblastic lymphoma and establishment of an immediate chemotherapeutic regimen, with rapid remission of compression symptoms. Conclusions: Plasmoblastic lymphoma is a very uncommon, difficult to diagnose, and aggressive disease. The presented case represents the first rare mediastinal plasmoblastic lymphoma in a human immunodeficiency virus-/human herpesvirus-8-negative patient. Pathologists should be aware that this tumor does appear in sites other than the oral cavity. Fine-needle aspiration biopsy is a low-cost, repeatable, easy-to-perform technique, with a high diagnostic accuracy and with very low complication and mortality rates. Fine-needle aspiration biopsy could represent the right alternative to surgery in those patients affected by plasmoblastic lymphoma, being rapid and minimally invasive. It allowed establishment of prompt medical treatment with subsequent considerable reduction of the neoplastic tissue and resolution of the mediastinal syndrome.