We evaluated the hypercapnia response test as a weaning outcome predictor from mechanical ventilation in patients with chronic obstructive pulmonary disease (COPD). We studied 44 COPD intubated patients considered ready for a weaning trial. The hypercapnia test was based on the modified method of re-inhalation of expired air. Through the hypercapnic test we calculated the ratio of the change in minute volume (V_E) to the change in P_aCO₂ (DV_E/DP_aCO₂), the change in airway occlusion pressure at 0.1 seconds of inspiration (P_0.1) to change in P_aCO₂ (DP_0.1/DP_aCO₂), the ratio of the change in P_0.1 to baseline P_aCO₂ (DP_0.1/P_aCO₂) and the ratio of the change in V_E to baseline P_aCO₂ (DV_E/P_aCO₂). Nineteen patients were successfully weaned and 25 patients failed. No differences in baseline clinical characteristics were found between the two groups. Weaning failure COPD patients had lower DP_0.1/DP_aCO₂ (0.19±0.11 and 0.34±0.20 cm H₂O/mmHg respectively, P=0.006) and lower DV_E/DP_aCO₂ (0.21±0.15 and 0.40±0.22 l/min/mmHg respectively, P=0.002) than successfully weaned patients. The area under the receiver operating characteristic curve to discriminate weaning outcome was for the baseline P_aCO₂ 0.81 (95% confidence interval: 0.66 to 0.91), hypercapnic P_aCO₂ 0.76 (0.61 to 0.88), hypercapnic drive response 0.74 (0.59 to 0.86), hypercapnic ventilatory response 0.76 (0.60 to 0.87), DP_0.1/P_aCO₂ 0.76 (0.60 to 0.87) and for the DV_E/P_aCO₂ 0.81 (0.67 to 0.91). COPD patients with weaning failure have a significantly more blunted response to the hypercapnia response test than weaning success patients. This test could be useful to predict weaning failure patients if the combined values of the hypercapnic drive and hypercapnic ventilatory response were below the threshold values.