Background: It was reported that nearly twenty percent of all initial weaning trials in mechanically ventilated chronic obstructive pulmonary disease patients failed, which may lead to prolonged mechanical ventilation and expose the patient to hazardous complications such as ventilator associated pneumonia, critical illness neuromuscular abnormalities and ICU psychosis rather than the complications of mechanical ventilation itself. Methods: This study was carried out at the Respiratory Intensive Care Unit of Chest Department, Zagazig University Hospitals from May 2013 to May 2015. It included Mechanically ventilated chronic obstructive pulmonary disease patients due to acute respiratory failure who underwent first weaning trial using two hours of spontaneous breathing trial through T piece. They were 60 patients, 44 males and 16 females with an age range from 41 to 65 years and a mean age of 54.23 ±6.41 years. At the end of the first weaning trial, patients were classified into two groups according to weaning outcome: Group I: (successful weaning) as a control group they were (20) patients and Group II: (failed weaning) they were (40) patients. Various risk factors were assessed including electrolyte imbalance, nutritional state, delirium, weaning induced myocardial ischemia and impaired thyroid function beside calculation of APACHE II score to assess illness severity. Results: This study reported significant risk factors for weaning failure including: malnutrition (62.5%), electrolyte imbalance (42.5%), myocardial ischemia (37.5%), hypoalbuminemia (32.5%), hypothyroidism (25%), delirium (20%) and overfeeding (17.5%) while in 5% of the studied patients no identified risk factor was observed. In this work, multiple regression analysis isolated two independent risk factors for weaning failure in COPD patients including, TSH level >2.65 mIU/ml and impaired nutritional status, with P value = (0.018, 0.048) respectively. Conclusions: 1-Myocardial ischemia, delirium, hypomagnesemia, hypophosphatemia and VAP could be considered as important risk factors for weaning failure, however high TSH level >2.65 mIU/ml and abnormal nutritional state were the most valuable independent predictors for weaning failure. 2-An increase in the degree of severity of illness on ICU admission APACHE II score), previous mechanical ventilation and longer duration of mechanical ventilation could intensify the risk for weaning failure. 3-RSBI below 85 breaths/min/L may increase the rate of weaning success.(guided by