Objective <p>Currently, the application of single-port inflatable mediastinoscopic esophagectomy in patients with locally advanced esophageal squamous cell carcinoma receiving neoadjuvant chemoimmunotherapy is relatively rare. This study aims to compare the clinical efficacy of single-port inflatable mediastinoscopic esophagectomy with that of thoracoscopic esophagectomy for locally advanced esophageal squamous cell carcinoma following neoadjuvant chemoimmunotherapy.</p> Methods <p>We retrospectively analyzed the perioperative data of 118 patients who underwent minimally invasive esophagectomy. Among them, 80 patients underwent thoracoscopy esophagectomy, and 38 patients underwent single-port inflatable mediastinoscopy esophagectomy. The number of mediastinal lymph nodes dissected, incidence of postoperative complications, and survival period were compared between the two groups.</p> Results <p>The results revealed that the number of mediastinal lymph nodes dissected was similar between the two groups (<i>p</i> = 0.185); In terms of postoperative complications, the incidence of pneumonia was significantly lower in the single-port inflatable mediastinoscopic esophagectomy group than in the thoracoscopic esophagectomy group (<i>p</i> = 0.038), but the incidence of hoarseness was higher in the single-port inflatable mediastinoscopic esophagectomy group than in the thoracoscopic esophagectomy group (<i>p</i> = 0.049). Moreover, there were no significant differences in recurrence patterns, overall survival, or disease-free survival between the two groups.</p> Conclusions <p>The results suggest that single-port inflatable mediastinoscopic esophagectomy is a safe and reliable option for patients with locally advanced esophageal squamous cell carcinoma who have received neoadjuvant chemoimmunotherapy.</p>