The objective of this study was to determine the toxicity and the efficacy of the combination of cisplatin, etoposide, 5-fluorouracil (5-FU) and folinic acid in the treatment of patients with advanced squamous cell carcinoma of the esophagus. Patients received cisplatin 80 mg/m(2) i.v. on day 1, etoposide 125 mg/m(2) i.v. on day 1 and etoposide 200 mg/m(2) p.o. on days 3 and 5, 5-FU 375 mg/m(2)/day continuously i.v. combined with folinic acid 30 mg p.o. 6 times per day on days 1--4. Courses were repeated every 4 weeks until progression or up to a maximum of 6 courses. Patients were evaluated for response after every two courses. Sixty-nine patients received a total of 291 courses (median 4, range 1--6). The hematological toxicity consisted of leukocytopenia grade 3 or 4 in 17 and 16% of patients, respectively. Leukocytopenic fever was seen in 19% of patients. Thrombocytopenia grade 3 or 4 was seen in 13 and 7% of patients, respectively. Non-hematological toxicity consisted of nausea/vomiting grade 3 in 32%, diarrhea grade 3 in 6% and mucositis grade 3 or 4 in 23% of patients. The overall response rate was 34% (complete response 4%, partial response 30%) and the median time to progression was 7 months in 13 patients who received no additional treatment. The median survival for all patients was 9.5 months with a 1-year survival rate of 36%. Ten patients with initially locally unresectable disease (N=2) or celiac or supraclavicular lymph node metastases (N=8) who received additional treatment (esophageal resection in seven patients and radiotherapy in three patients) after they had responded to chemotherapy had a 3-year survival of 50%. We conclude that the combination cisplatin and etoposide combined with 5-FU and folinic acid is a safe and active regimen for patients with advanced squamous cell carcinoma of the esophagus. Mucositis is the most prevalent toxicity.