Background: Neoadjuvant therapy could significantly improve survival for patients with locally advanced esophageal cancer. However, postoperative complications and recurrence are still urgent problems to be solved. Anlotinib was an effective second-line monotherapy for ESCC in China and the combination therapy might be a promising strategy. Nab-paclitaxel plus cisplatin as first-line therapy exhibited moderate efficacy in ESCC patients. This study was to investigate the efficacy and safety of nab-paclitaxel and cisplatin combined with anlotinib as neoadjuvant treatment for ESCC. Methods: ESCC patients with preoperative clinical stage II-III and all patients who can receive radical surgery were recruited in this study. Eligible patients received anlotinib (12mg, po, d1̃14, q3w) combined with nab-paclitaxel (175mg/m², iv, q3w) and cisplatin (20mg/m², iv, d1̃3, q3w) for 2 cycles during neoadjuvant therapy. 4 weeks after the end of neoadjuvant therapy, the patients underwent radical surgery after exclusion of contraindications to surgery. Tumor response was assessed by investigator according to RECIST version 1.1 using CT scans at baseline and within 2 weeks before surgery. The calculated sample size was 62. The primary endpoint was ORR, secondary endpoints were R0 resection rate, DFS, OS, DCR and safety. Results: From Apr 2021 to Dec 2021, a total of 26 eligible patients were enrolled. Among them, 17 patients underwent surgery after completing 2 cycles of neoadjuvant therapy, 3 patients chose other treatment options, and 6 patients are still receiving neoadjuvant therapy. patients who had received surgery (n = 17) were included in this analysis. In best overall response assessment, there were 4 CR (23.5%), 11 PR (64.7%) and 2 SD (11.8%). Consequently, ORR was 88.2% (95%CI: 63.6̃98.5%) and DCR was 100.0% (95%CI: 80.5̃100.0%). At the data cut-off date, 17 patients (100.0%) had underwent R0 resection. Among them, 4 patients (23.5%) were confirmed to be pCR. And the median DFS was not yet available. The safety profile suggested that the most common treatment-emergent adverse events with the incidence > 10% were gastrointestinal reactions (65.4%), hypokalemia (19.2%), nausea (15.4%), liver damage (15.4%), myelosuppression (11.5%) and vomit (11.5%). No grade ≥3 adverse events were noted. Conclusions: Preliminary results suggested that anlotinib combined with nab-paclitaxel and cisplatin in neoadjuvant treatment of ESCC exhibited encouraging efficacy and manageable adverse events. The conclusion should be validated in more patients included subsequently.