The case involves a 71-year-old man. In July 2007, he began receiving maximum androgen blockade (MAB) therapy at the urology department of his neighboring hospital because of prostate cancer. Serum PSA level was normalized by February 2009, but in February 2010 he began to suffer from dry cough. He was admitted to our hospital in May 2010 because chest radiography revealed a mass lesion in the left lung. A transbronchial tumor biopsy specimen showed small cell carcinoma. Despite a normal serum PSA level, however, prostate involvement enlarged and serum neuron-specific enolase (NSE) level elevated in response to MAB therapy. Immunohistochemical staining of lung biopsy and post-MAB prostate specimens were performed, and they revealed synaptophysin (+) with the feature of a neuroendocrine tumor. Because the immunohistochemical staining of the pre-MAB prostate specimen showed synaptophysin (-), we concluded that prostate cancer had undergone neuroendocrine differentiation after MAB therapy, and pulmonary metastasis occurred through the clinical course. After diagnosis, the patient was administered cisplatin and irinotecan. Pulmonary involvement was significantly improved, and serum NSE level was normalized. On the appearance of a small cell carcinoma in the lung during MAB therapy in a case of prostate cancer, neuroendocrine differentiation of the prostate cancer should be considered as the possible primary lesion.