Preoperative concurrent chemotherapy and radiotherapy can be highly effective but are often associated with significant rates of morbidity and even mortality. We studied the toxicity of continuous infusion of 5-fluorouracil (5-FU) and weekly paclitaxel combined with radiotherapy. Patients had histologic proof of local-regional carcinoma of the esophagus or gastroesophageal (GE) junction, a Karnofsky performance status of 70 or greater, and normal liver, renal, and bone marrow functions. Chemotherapy consisted of continuous infusion of 5-FU (300 mg/m2/d) for 5 days a week for 5 weeks, plus paclitaxel (45 mg/m2) given during 3 hours every week for 5 weeks. Based on the tumor location and its resectability, the total dose of concurrent radiation varied between 45 Gy and 50.4 Gy. Nine men and one woman, with a median age of 61 years, were evaluated. One had GE junction cancer, six had distal esophageal cancer, and three had midesophageal cancer. Weight loss, nausea, vomiting, and dysphagia of grades I and II were noted. The hematologic toxicity was mild. No patients required transfusion. There was no leukopenia or thrombocytopenia. None of the patients was hospitalized during chemoradiation; all patients completed treatment as outpatients. Five patients had subsequent surgical resections: one had a pathologically complete response, and two had a partial response (>90% necrosis). Continuous infusion of 5-FU plus paclitaxel given concurrently with radiotherapy was well tolerated. We plan to study this regimen further in upper gastrointestinal cancers.