Objective: To evaluate the efficacy and safety of Xiaoaiping combined with chemotherapy in the treatment of advanced esophageal cancer. Methods: This is a multi-center, randomized, open label and parallel controlled study. A total of 124 advanced esophageal cancer patients with Karnofsky Performance Status (KPS) score ≥60 and expected survival time≥3 months were enrolled. We adopted design and divided the patients into study and control group. The patients in study group received Xiaoaiping combined with S-1 and cisplatin. The control group received S-1 and cisplatin. Each group included 62 patients and 21 days as a treatment cycle. The efficacy and adverse events in patients of the two groups were observed and compared. Results: 57 patients in the study group and 55 in the control group were included in efficacy assessment. The response rate was 54.4% and 34.5% in the study group and control group, respectively(P<0.05). Disease control rates were 86.0% and 69.1%, respectively(P<0.05). The median progression-free survival (PFS) was 7.97 in the study group and 6.43 months in the control group(P<0.05). The median overall survival(OS) was 12.93 in the study group and 10.93 months in the control group(P<0.05). The most common adverse events in the two groups were nausea and vomiting, thrombocytopenia, anemia, neutropenia, liver damage, pigmentation, oral mucositis, renal impairment and diarrhea. The incidences of nausea, vomiting, thrombocytopenia, leukopenia, neutropenia and diarrhea in the study group were significantly higher than those in the control group(P<0.05). Conclusion Xiaoaiping combined with S-1 and cisplatin significantly increased response rate, and prolongedpatients′ survival in patients with advanced esophageal cancer.