Background: Removal of patients from mechanical ventilation (MV) has been termed liberation, discontinuation, withdrawal and most commonly weaning. Weaning covers the entire process of liberating the patient from mechanical support and from the endotracheal tube. Although weaning from MV is successful in most cases, the first attempt fails in 20% of patients. In addition, weaning accounts for over 40% of the total MV time, the proportion varying in function of the etiology of respiratory failure. Objective: The aim of this study was to evaluate the recent protocols of successful weaning from mechanical ventilation of critically ill patients, depending on central venous oxygen saturation, ultrasonographic assessment of diaphragmatic movement, and serial arterial blood gases to assess failure rate 48 hours after weaning. Patients and methods: This prospective randomized study included a total of 90 mechanically ventilated Egyptian patients of both sexes, ASA (I-II) attending at least for 48 hours at intensive care unit, AlAzhar University Hospitals. The included subjects were divided into three groups depending on method of monitoring; group A: serial arterial blood gases, group B: Central venous oxygen saturation and group C: Ultrasonographic assessment of diaphragmatic movement pre and post spontaneous breathing trial. All patients were subjected to daily monitoring of the following weaning parameters: static and dynamic compliances and inspiratory resistance, intrinsic positive end expiratory pressure (Auto PEEP) and Maximum inspiratory pressure (MIP). Results: There is highly statistically significant difference between patients as regard weaning outcome. As the group depended on normal ultrasonographic assessment of diaphragmatic movement, had the largest number of patients with successful weaning. Conclusion: Normal ultrasonographic assessment of diaphragmatic movement proved to be the most important criteria for successful weaning from mechanical ventilation.