Large cell neuroendocrine carcinoma (LCNEC) is a relatively new category of pulmonary neuroendocrine tumor. Although it was first detected in the lung, LCNEC has since been found in a variety of extrapulmonary sites. We now describe a patient who was diagnosed with LCNEC originating from the mediastinum, an extremely rare disorder. An increased serum concentration of alpha-fetoprotein (AFP) in the patient was reduced by chemotherapy in association with tumor shrinkage. Furthermore, the tumor was confirmed immunohistochemically to produce AFP. To our knowledge, this is the first report of a LCNEC that produces AFP.