Here, we report the four cases with metastatic esophageal squamous cell carcinoma pretreated with standard chemotherapy who then received salvage-line chemotherapy with oxaliplatin and 5-fluorouracil plus l-leucovorin (FOLFOX) at our institution. We identified four men following the mentioned regimen; their median age was 68.5 years (range, 65-76 years). All patients developed disease progression on 5-fluorouracil, cisplatin, and taxanes. Two patients achieved partial response; the other two achieved stable disease on receiving cisplatin-containing regimens as first-line therapy. The Eastern Cooperative Oncology Group performance statuses were 1 in three patients and 2 in one patient. The best response was partial response in one patient, stable disease in one, and progressive disease in two. For the two patients who achieved partial response or stable disease, the times to progression were 5.7 and 5.2 months and the overall survival times were 8.1 and 9.5 months, respectively. A grade 3 encephalopathy in one patient improved soon after chemotherapy discontinuation and supportive therapies. There was no treatment-related death. This is the first report suggesting the potential effectiveness of FOLFOX as salvage chemotherapy for metastatic esophageal cancer.