Thirteen patients with esophageal or gastroesophageal tumors with regional disease only were treated with sequential combined therapy. Weeks 1 to 6 continuous (24 hours) infusion 5-fluorouracil (5-FU) 300 mg/m2/d; weeks 6 to 10 or 12 infusional 5-FU administered concomitantly with radiation to the primary tumor site using standard fractionation with a cumulative median dose of 5000 rad; range 4400 to 6900 rad. Surgery was performed in five patients. All patients were evaluable for assessing response to the initial 5-FU infusion and 11/13 patients demonstrated tumor regression. Of 12 evaluable patients subsequently receiving combined infusional 5-FU and concomitant radiation, all 12 achieved complete clinical (10) or pathologic (two) tumor regression. Two of five patients having surgical resection had no pathologic evidence of tumor. All patients had relief of dysphagia within 1 week of initiating chemotherapy. Acute complications of therapy included stomatitis (two patients); hand-foot syndrome (two patients), and subclavian vein thrombosis (two patients). Stricture requiring periodic dilation occurred in three patients, and one patient developed a tracheoesophageal fistula at 36 months. Local control was maintained in 12/13 evaluable patients. Four of 13 patients were alive and without disease at 12 to 46 months. Nine patients died of distant metastases at 6 to 40 months. Median survival for the whole group was 16 months. Ten of the 13 patients (77%) survived for more than 1 year and 3/13 (22%) survived more than 3 years. This pilot study demonstrates the activity of 5-FU administered on an infusion schedule in both squamous and adenocarcinoma of the esophagus and the capacity to deliver infusional 5-FU throughout standard fractionation radiation. The local control and survival data may provide a basis for expanded Phase II trials, and a comparative trial against surgery alone might also be justified.