Undifferentiated carcinoma of the oral cavity is a rare and possibly fatal malignant neoplasm. We present here a case of undifferentiated carcinoma of the oral tongue, which responded well to chemotherapy with cisplatin, 5-fluorouracil, and cetuximab. A 59-year-old man was referred to our hospital for a large tumor of the tongue. Physical examination revealed an ulcerative tumor, approximately 50 mm in diameter, on the right edge of the tongue and swelling of multiple cervical lymph nodes; therefore, the clinical diagnosis was tongue cancer (T4aN2bM0). The histological diagnosis from a biopsy specimen was undifferentiated carcinoma; we tested the sample for human papilloma virus immunoreactivity, which was positive. The patient then underwent chemotherapy with cisplatin, 5-fluorouracil and cetuximab. The tumor's size decreased markedly after two courses of chemotherapy, but the treatment was stopped due to the patient' various mental problems and pneumonia; he died 6 months after the initial visit. Our encounter with this patient suggests that cetuximab treatment is a good option for HPV-positive undifferentiated carcinoma of the oral tongue.