We previously demonstrated that muscle fibers become unable to fire action potentials in both patients and an animal model of acute quadriplegic myopathy (AQM). In the animal model, skeletal muscle is denervated in rats treated with high-dose corticosteroids (steroid-denervated; SD), and muscle fibers become inexcitable despite resting potentials and membrane resistances similar to those of control denervated fibers that remain excitable. We show here that unexcitability of SD fibers is due to increased inactivation of sodium channels at the resting potential of affected fibers. A hyperpolarizing shift in the voltage dependence of inactivation in combination with the depolarization of the resting potential induced by denervation results in inexcitability. Our findings suggest that paralysis in the animal model of AQM is the result of an abnormality in the voltage dependence of sodium channel inactivation.