Previous studies in isolated muscles have shown that decreases in muscle length reduce the loss of force resulting from fatigue in response to repeated maximal stimulations. However, increases in end-expiratory lung volume (EEV), which presumably decrease the length of the inspiratory muscles, appear to make the inspiratory muscles more susceptible to fatigue. To address this paradox, we studied the influence of changes in EEV on inspiratory muscle fatigue resulting from repeated maximal voluntary inspirations for 15 min in normal humans. Tidal volume and breath timing were constant between runs. Fatigue runs were compared with atmospheric, positive or negative pressures applied to the mouth, sufficient to change EEV by approximately +30% or -20% of inspiratory capacity. Although the maximal initial pressure-time product for the inspiratory muscles (PTmus) was reduced by increased EEV, sustainable PTmus was not significantly affected. In contrast, both initial and sustainable pressure-time products for the diaphragm were reduced at elevated EEV The rate at which the fatigue process developed was also reduced at increased EEV There were no significant effects of decreased EEV on any measured pressures. We conclude that when EEV is elevated, within a moderate range, sustainable inspiratory muscle pressure is preserved. However, the contribution of the diaphragm to inspiratory pressure development during fatigue may be uniquely compromised by increased EEV.