Intrapulmonary percussive ventilation (IPV) is a ventilatory technique that delivers bursts of high-flow respiratory gas into the lung at high rates, intended for treating acute respiratory failure and for mobilization of secretions. We performed a study, aimed at assessing the physiological response to IPV, on patients' breathing pattern, inspiratory effort, lung mechanics and tolerance to ventilation. Ten COPD patients underwent randomized trials of IPV through a face mask at different pressure/frequency combinations (1.2 bar/250 cycles/min; 1.8/250; 1.2/350; 1.8/350), separated by return to baseline (SB), using the IMP2 ventilator. In 5 patients we have also compared the physiological changes of IPV with those obtained during pressure support ventilation (PSV). Minute ventilation did not vary among the trials, but tidal volumes (VT) were significantly greater during 1.2/250, 1.2/350 and 1.8/350 compared to SB. The pressure time product of the diaphragm per minute (PTPdi/min) estimate of the diaphragm oxygen expenditure was also significantly reduced during 1.2/250 and 1.8/250 (209 cmH2O x s/min for SB vs. 143 and 125 for 1.2/250 and 1.8/250, respectively P < 0.05), as well as dynamic intrinsic end-expiratory pressure (PEEPi,dyn). Similar reduction in PTPdi/min were obtained also during PSV. Tolerance to ventilation and oxygen saturation were satisfactory and did not change during the different trials. In 5 normal subjects a prolonged apnea trial lasting > 2 min was also performed, without any significant decrease in SaO2 or subjective discomfort. In conclusion, IPV was able to guarantee an adequate ventilation, while inducing a significant unloading of the diaphragm during the "low-frequency" trials.