Dynamic hyperinflation loads the inspiratory muscles by increasing end-expitatory lung volume (EELV) and imposing intrinsic positive end-expiratory pressure (PEEPi), the latter behaving as an inspiratory threshold load (ITL). The major purpose of this study was to describe the independent effects of the imposed ITL and changes in operating lung volume on the perception of Inspiratory difficulty. In eight healthy subjects, Independent increases in EELV and ITL were induced by continuous positive airway pressure (CPAP) and external ITL applications, respectively; increase In both EELV and PEEPi (thus the imposed ITL) was induced by application of positive end-expiratory pressure (PEEP). The perceived inspiratory difficulty Increased significantly when either EELV or ITL was Increased, and was always greater during combined increase in EELV and the imposed ITL (during PEEP) than when either factor was Increased independently, suggesting that the imposed ITL and EELV each contribute independently to inspiratory difficulty. inspiratory difficulty of each subject under all conditions was then fitted into a step-forward multiple regression model. The imposed ITL was a significant contributor to inspiratory difficulty in all subjects and was the first parameter to be selected in six of the eight subjects, When the results of all the subjects were pooled, the imposed ITL alone explained 40% of variations in inspiratory difficulty. Adding the change In end-inspiratory lung volume (Delta EILV) to the model explained an additional 24% of variations in inspiratory difficulty. The coefficients (slopes) of the imposed ITL and Delta EILV were 0.21 +/- 0.02 cm H2O-1 and 0.051 +/- 0.006 %IC-1, respectively. It. is concluded that under our experimental conditions, the imposed ITL is a better predictor for explaining the variability of the perceived inspiratory difficulty than the operating lung volume.