Objective To explore the strategy of intrathoracic anastomosis in patients with esophageal squamous cell carcinoma when the proximal esophagus is dilated to different degrees and explore its mechanism. Methods We retrospectively reviewed the clinical data of patients who underwent esophagectomy between 2014 and 2017 in West China Hospital. The patients were divided into two groups including a significant dilatation group with inner mucosal phase diameter (IMPD)≥17.9 mm and a non-significant dilatation group with IMPD<17.9 mm. And the patients were divided into two groups (a layered manual anastomosis group and a stapled anastomosis group) according to anastomosis method and propensity score matching was applied to adjust for potential confounders. Results We finally included 654 patients. There were 206 patients with 158 males and 48 females at average age of 62.21±7.72 years in the layerd manual analstomosis group and 448 patietns with 377 males and 71 females at average age of 62.57±8.42 years in the stapled anastomosis group. We also used Masson trichrome staining to assess the collagen fiber content in the esophagus. Compared with layered manual anastomosis, the incidence of anastomotic leakage was higher in the significant dilatation group than that in the stapled anastomosis group (original cohort: 3.8% vs. 10.7%, P=0.093; propensity score-matched cohort: 1.4% vs. 15.3%, P=0.004). And there was no significant difference in anastomotic leakage b etween layered manual anastomosis and stapled anastomosis in the non-significant dilatation group (original cohort: 4.7% vs. 4.2%, P=0.830; propensity score-matched cohort: 4.8% vs. 4.0%, P=0.206). Moreover, the average collagen fiber area ratio was significantly lower in the significant dilation group than that in the non-significant dilatation group (P=0.045). Conclusion There is a significant reduction in collagen fibers in the proximal esophageal wall tissue of esophageal squamous cell carcinoma patients with a IMPD≥17.9 mm. Intrathoracic layered manual anastomosis effectively reduces postoperative anastomotic leakage in these patients.