Background: Taxane is one of the commonly used chemotherapy drugs for ESCC. Nab-paclitaxel, a small particle albumin-bound form of paclitaxel, showed potentially efficacy in metastatic ESCC. This randomized, controlled, multi-center study is conducted to evaluate the efficacy and safety of nab-paclitaxel plus cisplatin in neoadjuvant treatment of ESCC. Methods: Two hundred and two patients with resectable locally advanced ESCC which was located in the middle or lower third of the esophagus were enrolled and randomly assigned in a 1:1 ratio to receive neo-adjuvant chemotherapy or surgery alone. Patients were treated with either two 3-week cycles of nab-paclitaxel (125mg/m², iv, d1, 8) and cisplatin (75mg/m², iv, d1), followed by esophagectomy 4-6 weeks after neoadjuvant (the treatment arm) or directly underwent esophagectomy (the control arm). The primary endpoint was overall survival (OS), the secondary endpoints included 1-, 2-, and 3-year OS rate, 1-, 2-, and 3-year disease-free survival (DFS) rate, R0 resection rate, reduction stage rate, chemotherapy-related adverse events. Results: Between April 2019 and June 2021, we randomly assigned 67 patients, of whom 31 in the treatment arm and 33 in the control arm were analyzed. There was no difference in baseline characteristics between the two arms. In the treatment arm, 24 patients underwent R0 resection, and 2 did not undergo surgery although chemotherapy was completed. All patients in control arm underwent R0 resection. In the treatment arm, the pathological complete response (pCR) rate was 20.83%, the major pathological response (mPR) rate was 33.33%, and the down-staging rate was 58.33%. No difference in survival benefit was observed between the two arms. The 1- and 2-year DFS rates of the treatment arm and the control arm were 88.99% vs 75.58% (HR = 0.421, 95%CI: 0.087̃2.032, P = 0.281) and 88.99% vs 66.13% (HR = 0.387, 95%CI: 0.082̃1.833, P = 0.231), respectively. The 1-year and 2-year OS rates of the treatment arm and control arm were 93.21% vs 75.32% (HR = 0.293, 95%CI: 0.061̃1.409, P = 0.125) and 86.56% vs 75.32% (HR = 0.444, 95%CI: 0.115̃1.716, P = 0.239). The neoadjuvant chemotherapy was well tolerated. According to NCI-CTC AE V.5.0, the most common adverse events were hematological toxicity, including neutropenia (16.13%), anemia (3.23%) and hypoproteinemia (3.23%), no grade IV adverse events occurred. Conclusions: Nab-paclitaxel plus cisplatin for ESCC reveals a promising efficacy and safety, and has a tendency to prolong DFS and OS compared with surgery alone. The long-term results are worthy of further exploration. Clinical trial information: NCT03964753.