The chemotherapy regimen currently used for treating esophageal and gastric carcinoma has been either epirubicin, cisplatin, and fluorouracil (5-FU) or docetaxel, cisplatin, and 5-FU. Here, we report the efficacy and toxicity of doxorubicin, cisplatin, and 5-FU for only esophageal squamous cell carcinoma (ESCC). Between January 2000 and October 2008, a total of 41 ESCC patients with a distant metastasis were enrolled. The most common sites of metastasis were liver (26, 63.4%), lung (9, 22.0%), and bone (8, 19.5%). Doxorubicin was administered on day 1 at 30 mg/m(2) , cisplatin on days 1-5 at 14 mg/m(2)/day, and 5-FU on days 1-5 at 700 mg/m(2)/day. The median number of cycles was 2.0 (range 1-8). The dose intensities of doxorubicin, cisplatin, and 5-FU were 92.9, 92.4, and 92.5%, respectively. The overall response rate was 43.9%; one showed complete response, 17 showed partial response, 13 showed a stable disease, and 10 showed progressive disease (PD). The median survival time was 306 days (95% CI = 74-935) and the 1-year survival rate was 37.6%. Grade 3 neutropenia was seen in seven patients and grade 4 in one patient. Grade 3 fatigue, anorexia, mucositis, and diarrhea were observed in three, two, two, and one patient, respectively. This regimen is effective as a first-line therapy for ESCC with distant metastasis.