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Objective: To compare the clinical effectiveness of two approaches of minimally invasive esophagectomy (MIE) in esophagectomy patients. Materials and Methods: We retrospectively screened the perioperative data in a total of 49 patients who underwent MIE. Among them, 30 patients underwent thoracoscopy combined with laparoscopy (Group A), while the rest received mediastinoscopy combined with laparoscopy (Group B). Clinical effectiveness and postoperative complications were comparatively analyzed. Results: The patients with mediastinoscopy showed a shorter average surgical time, less blood loss during surgery, diminished drainage volume in the first 3 days after surgery, and reduced hospitalization time, compared with the patients with thoracoscopic approach (P < .05). However, the mediastinoscopic route seems to render a higher incidence of postoperative hoarseness than thoracoscopy combined with laparoscopy (P < .05). In mediastinal lymph node dissection, the number of right recurrent laryngeal nerve lymph nodes (RLN LNs) in mediastinoscopic route was significantly less than that of thoracoscopy (P < .05). Conclusion: Mediastinoscopy was less invasive, with shorter surgical time, faster recovery, and better patient comfort, although it had certain limitations in the dissection of right RLN LNs. It is beneficial to patients with poor pulmonary function and no obvious mediastinal lymphadenectasis. [ABSTRACT FROM AUTHOR]