Background: Esophageal squamous cell carcinoma (ESCC) is a kind of cancer with high incidence and high mortality in China, and there is no effective treatment at present. Camrelizumab as a single agent has shown a higher survival benefit in clinical studies of second-line treatment of ESCC, but the degree of tumor remission is limited. Therefore, anti-angiogenic drugs and low-dose chemotherapeutics were added to observe and evaluate the efficacy and safety of Camrelizumab combined with Apatinib and Irinotecan in the second-line treatment of advanced ESCC. Methods: This is a single-arm, multi-center, phase II study. Patients over 18 years old, male or female, with ECOG score of 0-2, who had received systemic first-line chemotherapy (including concurrent chemoradiotherapy for distant metastases within 6 months), and who were diagnosed as ESCC by histopathology or cytology were included in the study, there were no severe hematopoietic dysfunction, heart, lung, liver, kidney dysfunction and immune deficiency. Results: As of June 29, a total of 42 patients were enrolled, of which 16 patients can be evaluated for efficacy.Among the 16 patients, 5 were out of the group due to progress, intolerance and active withdrawal, while the rest were still in the process of clinical research. The baseline characteristics of 16 patients were as follows: most of the patients were male (75%) and the ECOG score was poor (ECOG 1-2, 93.75%). All the patients were ESCC, and the degree of tissue differentiation was moderate to low differentiation, moderate differentiation (50%), and the location of cancer was middle thoracic (37.5%); Most of the patients had not received radiotherapy (75.0%) or targeted drug therapy (87.5%); Most of the first-line chemotherapy regimens were paclitaxel plus platinum (85%), and 12.5% of the patients used fluorouracil plus platinum. Among the 16 patients, the best efficacy evaluation distribution was: 1 patient with CR, 8 patients with PR, 4 patients with SD, 2 patients with PD, ORR was 56.25%, DCR was 81.25%; the median PFS and OS were not reached. In terms of safety, the incidence of adverse reactions at any level is 75%, of which the most common adverse reactions are fatigue (50%), gastrointestinal reactions (25%) and hypertension (18.8%); adverse reactions above grade 3 are fever (12.5%), no new safety signals appeared. Conclusions: This is the first study to explore PD-1 inhibitors combined with anti-angiogenesis inhibitors and DNA topoisomerase I inhibitors as second-line treatments for advanced ESCC. Camrelizumab combined with Apatinib and Irinotecan as a second-line treatment has shown encouraging clinical efficacy and acceptable safety, and may be a favorable option for patients with advanced ESCC. A further phase III randomized trial is needed. Clinical trial information: ChiCTR2000028857.