Background: Our previous phase I study (Radiother Oncol 2008,87:398) provided evidence that definitive chemoradiotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF-R) was tolerable and active in patients with advanced esophageal cancer (AEC). This phase II study was conducted to confirm the efficacy and toxicity of DCF-R in AEC. Methods: Patients with previously untreated carcinoma of the thoracic esophagus who had T4 tumors, M1 lymph-node metastasis, or both received an infusion of docetaxel (35 mg/m²) and an infusion of cisplatin (40 mg/m²) on day 1 and a continuous infusion of 5-fluorouracil (400mg/m²/day) on days 1-5, every 2 weeks, plus concurrent radiation (RT). The total RT dose was initially 61.2, but was lowered to multiple-field irradiation with 50.4 Gy to decrease esophagitis and late toxicity. Consequently, the number of cycles of DCF administered during RT was modified from 4 to 3. After DCF-R, patients received at least 2 cycles of DCF (docetaxel 40 mg/m² on day 1, cisplatin 60 mg/m² on day 1, and 5-fluorouracil 600 mg/m²on days 1-5, every 4 weeks). The primary endpoint was the clinical complete response rate (cCRR). Secondary endpoints were response rate (RR), progression free survival (PFS), overall survival, and safety. Results: 42 patients (36 men, 6 women) were enrolled. The median age was 62 years (range: 46-75). PS 0/1/2 was 14/25/3. TNM classification T4M0/non-T4M1LYM/T4M1LYM was 20/12/10. The total scheduled dose of RT 61.2Gy /50.4Gy was 12/30 patients. The RR was 90.5% and the cCRR was 52.4% (95% CI:37.3-67.5%). As of January 2013, the median PFS was 11.1 months and the median survival time was 23.1 months. Grade 3 or higher major toxicities comprised leukopenia (71.4%), neutropenia (57.2%), anemia (16.7%), febrile neutropenia (38.1%), anorexia (31.0%), and esophagitis (28.6%). There was one treatment-related death caused by aspiration pneumonia. Grade 3 or higher late toxicities comprised one pericardial effusion (Grade 4), one case of esophagitis (Grade 3), and one case of thoracic aortic aneurysm (Grade 3). Conclusions: DCF-R frequently caused myelosuppression, but was highly active and suggested be a promising regimen in AEC. Clinical trial information: 000002029.