We compared the efficacy of positive pressure ventilation (PPV) vs negative pressure ventilation (NPV) in providing ventilatory muscle rest for five normal subjects and six patients with chronic obstructive pulmonary disease (COPD). All participants underwent measurement of transdiaphragmatic pressure (Pdi), pressure time integral of the diaphragm (PTI), integrated diaphragmatic electromyogram (iEMG), minute ventilation (Ve), tidal volume (Vt), and end-tidal CO2 (etCO2) during 15 minutes of PPV and NPV. For each subject, ventilator adjustments were made to obtain Ve similar to levels measured during quiet breathing (QB). We found that the iEMG, Pdi, PTI, and average coefficient of variation of the tidal volume (CV-Vt) were consistently lower during PPV as compared with NPV (p = 0.01). The iEMG normalized for Ve and Vt was also significantly lower during PPV (p = 0.01). During PPV, subjects were mildly hyperventilated (lower etCO2 and higher Ve) compared with QB and NPV, but no significant correlation was noted between the change in etCO2 and the change in iEMG. The change in PTI was significantly correlated with the change in iEMG (p less than 0.01). We conclude that in the short term, PPV is more effective than NPV in reducing diaphragmatic activity. Positive pressure ventilation may be the preferred method of assisted ventilation in future studies of ventilatory muscle rest therapy.