Background: Non-thyroidal illness syndrome has been associated with diverse manifestations of critical illness in the ICU; it correlates significantly with severity of illness in clinically unstable patients. Objectives: The aim of the current work was to clarify the impact of thyroid dysfunction on weaning difficulty from mechanical ventilator in critically ill patients. Patients and Methods: This case –control observational study included a total of 50 patients received invasive mechanical ventilation (MV) with age > 18 years, attending at Internal Medicine & Critical Care and Anesthesia ICU departments, Faculty of Medicine, Assiut University Hospitals. This study was conducted between October 2020 to September 2021.  Full history taking and all routine laboratory investigations including complete thyroid panel were done at the time of mechanical ventilation. Results: Out of the studied patients; 33 (66%) patients were males. The most common causes of ICU admission were cardiogenic shock (30%) and toxicity (30%); the mean simplified acute physiology score (SAPS-II) among enrolled patients was 65.18 ± 17.92. Based on thyroid function, it was found that majority (70%) of patients have normal thyroid status while 15 (30%) has euthyroid sick syndrome (ESS) and all of them have low T3. Patients with ESS had significantly higher body mass index and SAPS-II. (p=0.001;0.06 respectively) Also, diaphragmatic dysfunction was significantly higher among patients with ESS (P=0.02) who showed longer duration of mechanical ventilation (p=0.03) and hospital stay(p=0.02). Conclusion: It could be concluded that critically ill patients who are admitted to intensive care units are vulnerable to develop euthyroid sick syndrome. ESS can increase the difficulty of weaning from mechanical ventilation and affect the outcome.