High flow nasal cannula (HFNC) has been shown to improve extubation outcomes in patients with hypoxemia, but the role of HFNC in weaning patients with chronic obstructive pulmonary disease (COPD) with hypercapnia from invasive ventilation is unclear. We compared the effects of HFNC to noninvasive ventilation (NIV) on postextubation vital signs and arterial blood gases (ABGs) among patients with COPD. Other outcomes included comfort scores, need for bronchoscopy, use of pulmonary medications, and chest physiotherapy. Forty-two COPD patients who had persistent hypercapnia at extubation were assigned randomly to receive HFNC (22) or NIV (20). Twenty patients in each group were enrolled for per-protocol analysis with regard to primary outcomes. Vital signs and ABGs before extubation were similar between groups. At 3 hr after extubation, pH in the NIV group was lower than HFNC group (7.42 ± 0.06 vs. 7.45 ± 0.05, p = 0.01). At 24 hr after extubation, patients' mean arterial pressure (82.97 ± 9.04 vs. 92.06 ± 11.11 mmHg, p = 0.05) and pH (7.42 ± 0.05 vs. 7.46 ± 0.03, p = 0.05) in the NIV group were lower than in the HFNC group. No significant differences were found at 48 hr after extubation. In the HFNC group, comfort scores were better (3.55 ± 2.01 vs. 5.15 ± 2.28, p = 0.02) and fewer patients needed bronchoscopy for secretion management within 48 hr after extubation (2/22 vs. 9/20, p = 0.03). HFNC is a potential alternative to NIV to wean hypercapnic COPD patients with regard to vital signs and ABGs, HFNC improved patients' comfort and secretion clearance.