Abstract Background SMP-ESCC is a rare subtype of esophageal cancer. Esophagectomy after neoadjuvant therapy became the standard treatment. However, there are still no studies comparing SMP-ESCC and single lesion esophageal squamous cell carcinomas (SL-ESCC) after neoadjuvant therapy. Our study aimed to analyze the differences of clinicopathological features and prognosis between SMP-ESCC and SL-ESCC. Methods All patients who received neoadjuvant therapy (Platinum-based chemotherapy regimen with or without radiotherapy at a total dose of 41.4-50.4 Gy/23-28 times) and plan esophagectomy were consecutively collected from January 2019 to March 2023. SMP-ESCC was defined as multiple lesions in the esophagus found at the time of diagnosis by endoscopy, with lesions more than 1 cm apart by normal mucosa, and diagnosed by pathology as squamous carcinoma or Tis. The cohort was divided into two groups (SMP-ESCC vs. SL-ESCC) with a 1:1 ratio through propensity score matching, and the differences in clinicopathological features and prognosis were compared. Results A total of 926 patients were enrolled, 58 (6.4%) patients had the type of SMP-ESCC. SMP-ESCC had higher pN stages (p<0.001), and a lower rate of pathological complete response (13.8% vs. 29.4%, p=0.016). SMP-ESCC had a poorer OS (49.8% vs. 65.0%, p=0.020) and DFS (21.1% vs. 61.0%, p<0.001) (Figure A-B). After matching, SMP-ESCC had a poorer 3-year DFS (33.5% vs. 60.9%, p=0.020) and a trend of poorer OS (51.0% vs. 71.7%, p=0.086) (Figure 1 C-D). Multivariate Cox regression analysis indicated that SMP-ESCC was an independent risk factor for OS (HR: 2.258, 95%CI: 1.006-5.068, p=0.048) and DFS (HR: 2.175, 95%CI: 1.157-4.092, p=0.016). Conclusion SMP-ESCC had a poorer response to neoadjuvant therapy compared to patients with SL-ESCC. And SMP-ESCC was an independent risk factor for OS and DFS, leading to a poorer prognosis. Therefore, SMP-ESCC need more rational and effective treatment in the perioperative period.