Background: Immunotherapy, particularly with anti-PD-1/PD-L1 antibodies, has shown therapeutic efficacy in various malignancies. Compared with chemotherapy, anti-PD-1 antibody monotherapy improved the median overall survival in advanced or metastatic esophageal cancer. The combination of an anti-PD-1/PD-L1 antibody with an angiogenesis inhibitor has shown efficacy in many cancers which including esophageal cancer. The purpose of this study is to investigate the efficacy and safety of anlotinib plus PD-1 inhibitors as chemo-free therapy during the treatment of esophageal cancer in the real world setting. Methods: This prospective, multicenter real-world study (NCT04966611) evaluated the efficacy and safety of anlotinib plus PD-1 inhibitors in the chemo-free therapy setting for advanced or metastatic esophageal cancer patients (pts). Primary endpoint was evaluation of PFS (progression-free survival), and secondary endpoints included ORR (objective response rate), DCR (disease control rate) and OS (overall survival). The response to treatment was evaluated according to RECIST version 1.1. In addition, adverse events were evaluated by CTCAE v5.0. Results: Between May 2020 and Dec 2021, 50 pts were enrolled. 45 comprised the evaluable population. In the full analysis set, 44 had squamous cell and 1 patient had adenocarcinoma histology. 29 (64.4%) of 45 pts were male. 10 (22.2%) had an ECOG performance status of 0, 32 (71.1%) status of 1 and 3 (6.7%) status of 2. Twenty (44.4%) pts had distant metastases and 29(64.4%) pts had comorbidities. 15 pts had previously used anti-PD-1/PD-L1 antibody or vascular targeting drugs, of which 5 cases had combined the two drugs. Among all evaluable pts, 5(11.1%) pts received first-line, 27(60.0%) second-line and 13(28.9%) third & above line therapy. Among all pts, 1 patient achieved complete response (CR), 16 pts partial response (PR), 25 pts stable disease (SD), illustrating an ORR of 37.8% and a DCR of 93.3%. In the first line therapy, ORR was 60.0%, DCR was 100%.In the second line therapy, ORR was 37.0%, DCR was 96.3%. In the third & above line, ORR with 30.8%, DCR with 84.6% was observed. Median PFS was not reached. Treatment related adverse events (trAEs) were reported in 24 pts(53.3%). No patient had grade 3 or more trAEs. Conclusions: Anlotinib plus PD-1 inhibitors in chemo-free therapy for advanced or metastatic esophageal cancer was active and showed excellent tumor response and was generally well tolerated. Further investigation is required in a larger real-world cohort to validate the benefit of anlotinib plus PD-1 inhibitor in esophageal cancer. Clinical trial information: NCT04966611.