Twenty-one consecutive patients with squamous cell carcinoma of the esophagus (EC) were referred, with advanced Stage III disease in nine patients, severe pulmonary/cardiac disease in five patients, and postsurgical recurrences or metastatic disease in seven patients. They were treated with one to four courses of 5-fluorouracil (5-FU) + mitomycin C, alternating with 5-FU + cisplatin (5-FU: 1,000 mg/m2/24 × 96-h infusion; Mitomycin C: 10 mg/m2 i.v.; cisplatin: 75 mg/ m2 i.v.) simultaneously with 3,000–5,000 cGy of local radiotherapy (RT) in 3.5–5.5 weeks. These doses of chemotherapy (CT) and RT were generally well tolerated except for prolonged thrombocytopenia in two patients, pancytopenia in one, pulmonary fibrosis in one, and acute renal failure in one. Six patients were alive and free of disease 8–40 months (median, 16 months; mean, 21.5 months) after initiation of treatment. Two additional patients died of unrelated causes without evidence of viable disease at autopsy. Our experience confirms the rapid and sustained palliation of dysphagia and pain obtained within 7–14 days after initiation of treatment. Mean survival of patients receiving one to two courses of CT and 4,000 cGy) and CT (three to four cycles) are tolerated with acceptable morbidity and could provide good palliation and sometimes prolonged disease-free status in those patients with EC who are considered inoperable because of advanced disease or medical reasons.