BACKGROUND A 96-hour infusion schedule of paclitaxel demonstrates tolerability and antitumor activity in lung cancer and breast cancer refractory to short-duration infusion paclitaxel. Given the activity of paclitaxel in esophageal cancer, a phase II trial of 96-hour infusion paclitaxel in esophageal cancer was undertaken. METHODS Both adenocarcinoma and squamous cell histology were included. Paclitaxel was administered at 140 mg/m2 over 96 hours every 21 days. Patients who had metastatic disease to the liver and transaminases greater than two times normal value received 120 mg/m2. Response to treatment was evaluated after the first two cycles and subsequently every third cycle. RESULTS Ten men and four women were entered. All were eligible for response and had stage IV disease. Thirteen patients were previously treated. All 13 received prior short-duration paclitaxel-containing chemotherapy regimens. Eleven patients had adenocarcinoma and three squamous cell cancer. Patients completed a mean of two cycles (range one to eight) prior to disease progression. No major responses were observed. Toxicity was minimal and included grade 3/4 neutropenia in 14% of patients. One patient with adenocarcinoma demonstrated stable disease for 28 weeks. CONCLUSIONS No major activity was observed in a population of previously treated patients. Ninety-six-hour paclitaxel in metastatic esophageal cancer is generally well tolerated with minimal toxicity; however, it is ineffective in previously treated patients. Further evaluation of this schedule of paclitaxel in combination with concurrent radiotherapy, where its radiosensitizing potential may be useful, is ongoing in locally advanced esophageal cancer.