Phrenic motoneuron firing rates during brief inspiratory resistive loading (IRL) are high, and nearly all the motoneurons are recruited. Diaphragmatic fatigue has been difficult to demonstrate during IRL. Furthermore, evidence from studies in limb muscles has shown variable motoneuron responses to prolonged high-intensity loads. We studied phrenic motoneuron firing rates before, during, and after prolonged IRL in anesthetized rabbits. Of 117 phrenic axons, only 2 axons were not recruited; 41 axons were silent during unloaded breathing but were recruited at higher loads. Silent axons showed a more rapid increase in firing rate as the load increased. Phrenic motoneuron firing rates increased throughout the period of loading, whereas airway pressure swings did not. After prolonged IRL, higher motoneuron firing rates were needed during brief loads to produce the same airway pressure. No evidence of a decline in motoneuron firing rates was seen at any point. We conclude that the respiratory muscles can be shown to demonstrate physiological responses consistent with fatigue during prolonged IRL, and activation rates are high and remain so throughout this prolonged loading.