e compared the behavior of motor neurons innervating their physiological muscle targets with motor neurons from the same spinal segment whose axons were surgically redirected to remnant muscles (targeted muscle reinnervation). The objective was to assess whether motor neurons with nonphysiological innervation receive similar synaptic input and could be voluntary controlled as motor neurons with natural innervation. For this purpose, we acquired high-density EMG signals from the biceps brachii in 5 male transhumeral amputees who underwent targeted reinnervation of this muscle by the ulnar nerve and from the first dorsal interosseous muscle of 5 healthy individuals to investigate the natural innervation of the ulnar nerve. The same recordings were also performed from the biceps brachii muscle of additional 5 able-bodied individuals. The EMG signals were decomposed into discharges of motor unit action potentials. Motor neurons were progressively recruited for the full range of submaximal muscle activation in all conditions. Moreover, their discharge rate significantly increased from recruitment to target activation level in a similar way across the subject groups. Motor neurons across all subject groups received common synaptic input as identified by coherence analysis of their spike trains. However, the relative strength of common input in both the delta (0.5–5 Hz) and alpha (5–13 Hz) bands was significantly smaller for the surgically reinnervated motor neuron pool with respect to the corresponding physiologically innervated one. The results support the novel approach of motor neuron interfacing for prosthesis control and provide new insights into the role of afferent input on motor neuron activity. SIGNIFICANCE STATEMENT Targeted muscle reinnervation surgically redirects nerves that lost their target in the amputation into redundant muscles in the region of the stump. The study of the behavior of motor neurons following this surgery is needed for designing biologically inspired prosthetic control strategies. Moreover, targeted muscle reinnervation offers a human experimental framework for studying the control and behavior of motor neurons when changing their target innervated muscle fibers and sensory feedback. Here, we show that the control of motor neurons and their synaptic input, following reinnervation, was remarkably similar to that of the physiological innervation, although with reduced common drive at some frequencies. The results advance our knowledge on the role of sensory input in the generation of the neural drive to muscles and provide the basis for designing physiologically inspired methods for prosthesis control.