Tension in the respiratory muscles and the subsequent intrathoracic subatmospheric pressure swing plays a role in respiratory effort sensation. However, the role of a diaphragmatic fatiguing process in the genesis of this sensation has not been examined. Therefore, we studied the effect of fatiguing contractions of the diaphragm on inspiratory effort sensation (IES) in 6 normal male subjects during inspiratory resistive loading. Four diaphragmatic fatiguing and 4 diaphragmatic nonfatiguing patterns were developed for each subject. These 8 patterns were imposed in random order for 10 breaths (50 s) with duty cycle and tidal volume fixed. The presence or absence of a diaphragmatic fatiguing process was confirmed by analysis of the high to low ratio of the electromyographic signal from an esophageal electrode. Subjects scored their IES immediately after each run using a modified Borg scale. There was a very strong correlation between IES and esophageal pressure (Pes) expressed as a percentage of maximal inspiratory esophageal pressure (Pes/Pesmax %) (r = 0.88, p less than 0.001). However, IES was independent of the presence of a diaphragmatic fatiguing pattern. Furthermore, there was no difference in the slope or intercept of the regression lines relating IES to Pes/Pesmax % when fatiguing and nonfatiguing runs were analyzed separately. We conclude that the severity of IES during resistive loading held for 50 s is independent of the development of diaphragmatic fatigue.