BACKGROUND: Patients with metastatic or recurrent esophageal squamous cell carcinoma (ESCC) have a poor prognosis. For decades, the most widely used first-line chemotherapy regimen for these patients has been the combination of 5-fluorouracil + cisplatin (CF). However, prognostic factors of CF as first-line chemotherapy for ESCC have not been clarified. METHODS: A total of 187 patients with metastatic or recurrent esophageal ESCC treated with CF at the National Cancer Center Hospital between January 2001 and December 2012 were enrolled in the study. The CF regimen comprised cisplatin (80 mg/m2) administered on day 1 and 5-fluorouracil (800 mg/m2) administered continuously on days 1-5, every 4 weeks. Multivariate Cox regression analysis was used to determine the potential prognostic factors. RESULTS: The median age of the patients was 62 (range 34-84) years. Metastasis and recurrence occurred in 116 and 71 of these patients, respectively. The overall response rate was 37.2%, with median progression-free and overall survival times of 4.8 and 10.4 months, respectively. In the multivariate analysis, higher serum C-reactive protein level and lower serum albumin level at the time of CF treatment initiation and number of metastatic sites were identified as independent prognostic factors for survival. CONCLUSIONS: The results of this study corroborate previous findings on the efficacy of CF and will aid physicians in clinical decision-making and individual patient risk stratification, as well as in the further development of chemotherapy regimens.