The patients with metastatic or recurrent esophageal cancer are incurable. A number of patients who progress after first-line chemotherapy may still be fit for second-line treatment. However, there is no currently established effective and tolerable salvage chemotherapy. We investigated the activity and tolerability of MIC in patients who had failed to prior chemotherapy for metastatic or recurrent esophageal squamous cell carcinoma. MIC (mitomycin 6 mg/m(2), ifosfamide 3 g/m(2), and cisplatin 50 mg/m(2)) was given in day 1 as an outpatient regimen and repeated every 3 weeks. All 32 enrolled patients were male with median age of 57 years. Prior esophagectomy had been performed in 21 patients (65.6%) and 11 patients (34.4%) were metastatic disease at initial diagnosis. Nineteen patients (59.4%) were treated with MIC as second-line chemotherapy. Prior first-line chemotherapy regimens consisted of 5-FU/cisplatin and capecitabine/cisplatin combinations. Overall response rate was 12.5% with no CR, and disease control rate was 37.5%. Grade 3/4 neutropenia was observed in 21 % of patients and grade 3/4 febrile neutropenia was seen in only one patient. There was no treatment-related mortality. Median PFS was 2.0 months (95%CI = 1.4-2.5) and the median OS was 5.2 months (95%CI = 3.3-7.0) with no significant difference between numbers of prior chemotherapy regimen. MIC chemotherapy has modest activity as a salvage regimen with tolerable toxicity, and could be one of the chemotherapy treatment options for patients with advanced or recurrent esophageal squamous cell carcinoma for whom previous chemotherapy has failed.