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Background The outcome in patients with chronic obstructive pulmonary disease (COPD) who need mechanical ventilation (MV) is altered by several factors such as severity of the disease, severity of acute exacerbation, advanced age, the cause of exacerbation, and development of complications. Aim This study aimed to assess the outcome of clinical phenotypes of MV COPD patients who were admitted to the respiratory ICU in 2014 and the influencing factors. Patients and methods This prospective study included 106 MV COPD patients. All patients underwent a thorough medical history, routine and specific investigations including: chest radiography, high-resolution computed tomography, serum immunoglobulin E, total and differential leukocytic count, serial arterial blood gases immediately before intubation, during MV and just before weaning. Results There were many predictors of bad outcome with statistical significance such as: older age (62.94±12.5 vs. 57.81±12.6 years), higher temperature on admission (37.48 ±0.67 vs. 37.20±0.42°C), higher serum of HCO3 on admission (42.5±4.5 vs. 38.9±7.8 mEq/l), longer duration of MV (12.05±4.4 vs. 4.8±1.84 days), higher last year number of exacerbations (1.94±0.9 vs. 1.47±0.6 times), with shorter duration from last exacerbation (40.4±1.2 vs. 50.5±2.04 days), dyspnea as the main presenting symptom, past history of MV, occurrence of complications during MV, emphysema phenotype (52.7 vs. 22.8%). Conclusion Past history of MV, emphysema phenotype, duration of MV, higher last year number of exacerbations, and shorter duration since the last exacerbation are reliable predictors of poor outcome and mortality in MV COPD patients with acute on top of chronic respiratory failure.