Prolonged reductions in muscle activity results in alterations in neuromuscular properties, however the time course of adaptations is not fully understood and many of the specific adaptations have not been identified. This study evaluated the temporal evolution of adaptations in neuromuscular properties during and following 3-wks of immobilization. We utilized a combination of techniques involving nerve stimulation and transcranial magnetic stimulation to assess changes in central activation of muscle, along with spinal (H-reflex) and corticospinal excitability (i.e. motor evoked potential (MEP) amplitude, silent period (SP)), and contractile properties in 10 healthy humans undergoing 3-weeks of forearm immobilization and 9 control subjects. Immobilization induced deficits in central activation (85±3 to 67±7% ) that returned to baseline levels 1-week after cast removal. The flexor carpii radialis (FCR) MEP amplitude increased greater than 2-fold after the first week of immobilization and remained elevated throughout immobilization and 1-week after cast removal. Additionally, we observed a prolongation of the SP 1-week after cast removal when compared to baseline (78.5±7.1 to 98.2±8.7 msec). The contractile properties were also altered, as the rate of evoked force relaxation was slower following immobilization (-14.5±1.4 to -11.3±1.0 %Peak Force/msec), and remained depressed 1-week after cast removal (-10.5±0.8 %Peak Force/msec). These observations detail the time course of adaptations in corticospinal and contractile properties associated with disuse, and illustrate the profound effect of immobilization on the human neuromuscular system as evidenced by the alterations in corticospinal excitability persisting 1-week following cast removal.