The purpose of this study was to determine the association between reduced fatigability typically observed in disused muscle and an improved resistance to the impairment of neuromuscular propagation. Endurance time of an isometric contraction sustained at 35% of maximum voluntary contraction (MVC) force and the fatigue-induced change in the evoked compound muscle action potential (M wave) were measured in the first dorsal interosseus muscle of human subjects before, during, and after 3 (n = 9) or 5 wk (n = 2) of immobilization. The immobilization procedure caused a substantial decline in the chronic electromyographic (EMG) activity (to 4% of control value) of the first dorsal interosseus muscle. Endurance time was found to be significantly correlated to the maintenance of M-wave amplitude during the fatigue task. However, neither of these variables was significantly affected by immobilization. Also, immobilization had no significant effect on the prefatigue values of MVC force and EMG or twitch contraction time or on the postfatigue changes in MVC force and EMG, M wave duration, twitch amplitude, and contraction time. In the unfatigued muscle, immobilization did cause an increase in twitch force (153%) and a decrease in M-wave amplitude (67%). It appears, therefore, that a healthy first dorsal interosseus muscle is generally resistant to adaptation when its use has been reduced for 3–5 wk by immobilization.