A prospective evaluation of the prevalence of CO2 retention and its relationship to lung mechanics and inspiratory muscle strength was carried out in 311 clinically stable patients with chronic obstructive pulmonary disease (COPD). Of these patients 32.8% had hypercapnia (PaCO2 greater than or equal to 43 mm Hg). PaCO2 was directly related to lung resistance (RL; r = 0.53) and inversely related to FEV1 (r = 0.53) and to an expression of the dead space/tidal volume ratio (1 - VD/VT) (r = 0.48). RL was found to be a major determinant of the mean intrathoracic pressure swing developed during inspiration (PI) at rest (r = 0.85). Maximal inspiratory pressure (PImax) was found to improve the predictive value for PaCO2 of several mechanical loads, with RL/PImax the best predictor (r = 0.57). The prevalence of hypercapnia increased from virtually 0 to 100% with increases in the RL/PImax value and was higher in the obese subjects at intermediate RL/PImax values, probably because of the burden placed on the respiratory muscles by chest wall mass loading. Our results show that chronic alveolar hypoventilation is likely to develop in COPD patients who have a combination of high inspiratory loads and inspiratory muscle weakness. hypercapnia may be one strategy available to avoid overloading of the inspiratory muscles leading to fatigue and possible irreversible failure.