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Introduction: Esophageal cancer is the sixth cause of cancer related deaths worldwide. Esophagectomy is the standard treatment for non-metastatic esophageal cancer, but is associated with high mortality and morbidity rates. We evaluated the mortality and complications following esophagectomy, and factors affecting it (including the surgical approach). Methods: This retrospective study was performed from 2006 to 2012; the data were collected from medical files of esophageal cancer patients who underwent surgical procedures at Iran's cancer institute and analyzed. Results: A total of 254 operated esophageal cancer patients entered this study. Patients included 105 males and 149 females, with a mean age of 65.70. Of all the operated patients, 121 (47.64%) underwent the trans-hiatal and 121 (47.64%) the transthoracic esophagectomy method, also 12 patients were operated by other surgical methods. Post-operative complications occurred in 61 patients (24.02%). Respiratory complications (20.08%) --including Adults Respiratory Distress Syndrome (9.45 %), pneumonia (6.30%) and ventilator dependency (4.33%) - were the most common complications. Other major complications were anastomosis leakage and fistula (6.30 %), atrial fibrillation (6.30 %), chylothorax (3.15%), bleeding requiring reoperation (1.97%) and pulmonary embolism (1.97 %). In-hospital mortality rate was 5.12 %. Pneumonia, ICU admission and intubation time were significantly higher in transthoracic than trans-hiatal method but mortality was not significantly different. ARDS, ventilator dependency and history of cardio-pulmonary disease were prognostic for in-hospital mortality. Conclusion: Although esophagectomy is a complex surgery and associated with multiple complications, in case of proper patient selection and experienced surgeons, both the transthoracic and trans-hiatal esophagectomy methods have appropriate results. [ABSTRACT FROM AUTHOR]