BACKGROUND/AIM: In this study, we assessed the safety and efficacy of combination therapy with S-1, oxaliplatin and leucovorin (SOL) in advanced esophageal squamous cell carcinoma (ESCC) patients. PATIENTS AND METHODS: Ten unresectable or recurrence ESCC patients, who had been previously treated with more than two regimens were included in this study. The treatment schedule comprised S-1 40-60 mg and fixed dose of leucovorin 25 mg together orally twice a day for one week, followed by one-week of rest. Oxaliplatin 85 mg/m was given as an intravenous infusion on day one, repeated every two weeks. RESULTS: Of the eight patients with measurable lesions, two patients with partial response (25%) and two with stable disease (25%) were observed. Disease control rate was 50%. Median progression-free survival and overall survival were 5.0 and 9.3 months, respectively. The main common adverse events were malaise (60%), decreased appetite (50%), peripheral sensory neuropathy (40%). CONCLUSION: SOL therapy showed promising antitumor activity with acceptable toxicity even for heavily pretreated ESCC.