BACKGROUND Interferon in combination with 5-fluorouracil has been shown to be active in squamous cell carcinoma (SCC) and adenocarcinoma (AC) of the esophagus. 13-cis-retinoic acid (CRA) has chemopreventive activity in SCC of the head and neck, and, in combination with interferon, has antitumor activity in SCC of the skin and cervix. METHODS The activity and toxicity of CRA and interferon-alpha-2a (IFN) in patients with advanced esophageal carcinoma was evaluated in a Phase II single institution trial. Patients had unresectable or metastatic AC or SCC of the esophagus. One prior chemotherapy regimen was allowed. IFN was given by daily subcutaneous injection at a dose of 3 million U and CRA was taken orally at a dose of 1 mg/kg/day in 2 divided doses. Treatment was given in cycles of 4 weeks and continued until documented disease progression. RESULTS Of the 19 patients entered, 15 were evaluable for response and toxicity. One patient was evaluable for response only and one patient was evaluable for toxicity only. Evaluable patients were predominantly male (15 patients), and had AC (13 patients). All had AJCC Stage IV disease and 12 were pretreated. Patients completed an average of two cycles of therapy (range, one to six cycles) prior to progression of disease. National Cancer Institute Common Toxicity Criteria Grade 3/4 toxicity was notable for nausea (25%) and fatigue (31%). No major objective responses were recorded. Eleven patients with AC and 3 patients with SCC had rapid progression of disease. One patient with AC was found to have a minor response for 22 weeks and 1 patient with AC had stable disease for 45 weeks. CONCLUSIONS This regimen had no significant activity in patients with advanced AC of the esophagus. Further evaluation of IFN plus CRA, using this dose and schedule, is not recommended. In comparison with prior trials of this therapy, a surprising amount of severe nausea and fatigue was observed in this trial.