Abstract: Objective To observe and compare the efficacy and safety of gemcitabine or fluorouracil combined with cisplatin in the second-line treatment of advanced esophageal squamous cell carcinoma. Methods Clinical data about advanced esophageal squamous cell carcinoma (ESCC) patients from January 2013 to October 2014 who received gemcitabine or fluorouracil combined with cisplatin as second-line chemotherapy in our hospital after failure to chemotherapy were retrospectively analyzed, its adverse reactions and curative effect were evaluated. Results Fifty-seven patients were evaluated. The response rates were 19.4% and 19.2%, the disease control rates were 58.1% and 53.8%, the median progression-free survival (PFS) were 3.0 (2.39-3.69) months and 4.4 (2.69-6.03) months, and the median overall survival (OS) were 6.0 (4.87-7.21) months and 7.6 (3.88-11.93) months in gemcitabine group and fluorouracil group, respectively, with no significant difference (P> 0.05). Toxicity was tolerable, and major adverse events were myelosuppression, nausea and vomiting in two groups. Conclusion Gemcitabine or fluorouracil combined with cisplatin as the second-line chemotherapy is effective in patients with advanced esophageal squamous cell carcinoma.