Background: Three-drug combination therapy based on cisplatin/fluorouracil might improve treatment efficacy for metastatic esophageal squamous cell carcinoma (ESCC), but at the risk of increasing toxicity. The study sought to identify factors associated with outcomes of metastatic ESCC in patients who were treated with three-drug combinations. Patients and Methods: One-hundred and thirteen patients with metastatic or recurrent ESCC who were treated with cisplatin/fluorouracil-based three-drug combination during 2000-2009 were studied. The prognostic impact of clinicopathological characteristics were evaluated by Cox proportional hazard regression analyses. Results: The third chemotherapeutic agents comprised of paclitaxel, docetaxel, and methotrexate in 76 (67%), 13 (12%), and 24 (21%) of patients, respectively. The overall response rate was 41%. The median overall survival (OS) was 8.5 months. Results of the Cox proportional hazard regression models showed that age >= 65 years, Eastern Cooperative Oncology Group performance status of 0 and 1, lymph node-only metastasis and baseline white blood cell (WBC) count