To evaluate the treatment outcome of radiotherapy combined with cis-diammine-glycolatoplatinum (nedaplatin) plus 5-fluorouracil (5-FU) for esophageal cancer. From January 2000 to December 2004, a total of 12 esophageal cancer patients with locally advanced and metastatic esophageal cancer (stages II-IVB) were treated with radiation therapy (50.4 Gy) combined with nedaplatin (80 mg/m(2), bolus infusion) and 5-FU (800 mg/m(2)/24 h, continuous infusion for 4 days) (NDP group). We compared the data with those of patients during the same period receiving a different chemotherapy regimen consisting of cisplatin (75 mg/m(2), bolus infusion) and 5-FU (1000 mg/m(2)/24 h, continuous infusion for 4 days) (n = 29, CDDP group) combined with the same radiation therapy. The median survival period was 11.5 months in the NDP group and 13.1 months in the CDDP group. The overall survival rates at 1-, 2-, and 3-years were 40%, 13%, and 13% in the NDP group and 56%, 42%, and 8% in the CDDP group (P = 0.2472), respectively. Grade III and IV leukocytopenia was observed in six (50%) and none of the patients in the NDP group and 14 (48%) and seven (24%) in the CDDP group, respectively. Grade III thrombocytopenia was observed in three (25%) in the NDP group and four (14%) in the CDDP group. Radiation combined with nedaplatin and 5-FU is a safe and effective method for treating esophageal cancer. We recommend that NDP should be used rather than dose-reduction of CDDP combined with 5-FU in patients with impaired renal function as indicated by low creatinine clearance value (40-60 mL/min).