Patients with severe COPD may be in a state of ventilatory muscle (VM) fatigue. In these patients, rapid and shallow breathing has been hypothesized to be a compensatory mechanism that prevents more severe fatigue from taking place. To test these hypotheses, we studied the effects of VM resting in a group of patients with severe COPD. Eleven clinically stable patients with COPD and chronic hypercapnia were studied. Six of them (group A) had a seven-day period of negative pressure-assisted ventilation (NPV), and five (group B) with similar functional characteristics served as a control group. Compared with a normal age-matched control group, both A and B groups exhibited significantly lower tidal volume (VT), inspiratory time (TI), total time of the respiratory cycle (Ttot) and TI/Ttot ratio, decrease in muscle strength, and greater electromyographic activity of diaphragm (EMGd) and parasternal muscles, but similar ventilation and VT/TI. After the study period, group A exhibited significant increase in VT, TI, and TI/Ttot (p < 0.05), and decrease in PaCO2 (p < 0.05), EMGd, and EMGint (p < 0.05 for both), and a slight but significant increase in maximal inspiratory pressure (MIP) (p < 0.05). These data suggest that NPV rests VM, increases their strength, and reduces hypercapnia in patients with severe COPD.