Few studies have focused on extubation outcome in patients with chronic obstructive pulmonary disease (COPD) requiring mechanical ventilation (MV). We conducted a study using prospectively collected data in a cohort of patients with COPD requiring invasive MV to identify variables associated with extubation failure. Use of noninvasive or invasive MV within 48 hours after extubation was defined as extubation failure. A total of 148 patients with COPD were studied. Extubation failure occurred in 35% of studied patients. Using multiple regression analysis, independent predictors of extubation failure were physiologic abnormalities measured by Simplified Acute Physiology Score II above 35 on intensive care unit (ICU) admission (odds ratio [OR], 3.88; 95% confidence interval [CI], 1.65-9.12), home noninvasive MV (OR, 12.99; 95% CI, 2.86-58.89), and sterile endotracheal aspirations on the day of extubation were predictors of success (OR, 0.23; 95% CI, 0.10-0.52). Despite high rate of extubation failure, survival to ICU discharge was 91% of the studied population. Extubation failure in patients with COPD remains high despite a successful spontaneous breathing on T piece. Simplified Acute Physiology Score II at ICU admission, home noninvasive MV, and isolated pathogens on quantitative cultures of tracheobronchial secretions within 72 hours preceding extubation were predictors of extubation failure in the study population.