We studied eleven patients during 14 attempts at weaning from mechanical ventilation to determine whether central ventilatory drive, measured as airway occlusion pressure 0.1 s after onset of inspiration (P 0.1), during spontaneous breathing before and during a brief hypercapnic challenge, could accurately predict the success or failure of the attempt. All patients were recovering from acute respiratory failure and could breathe spontaneously for 20 minutes on a T-piece but were judged clinically to be marginal weaning candidates. Minute ventilation (VI) and P 0.1 were measured while breathing spontaneously and were repeated during a hypercapnic challenge that raised end-tidal PCO2 approximately 10 mm Hg. Seven of the 14 weaning attempts were unsuccessful, requiring reinstitution of mechanical ventilation. Although the failure group had lower mean maximum inspiratory force and higher spontaneous respiratory rate, no threshold value separated the failure from the success group. Ventilation increased more during hypercapnic challenge in those patients whose weaning attempt was successful, but overlap of results between the two groups rendered this test inaccurate for predicting weaning success. In contrast, successfully weaned patients had greater augmentation of P 0.1 during hypercapnia, expressed as the ratio of P 0.1 during CO2-stimulated to P 0.1 during baseline values, than did those who failed weaning (p less than 0.005). This ratio succeeded, and was thus both specific and sensitive as a predictor of successful weaning from mechanical ventilation in these patients.