Small-fiber neuropathy (SFN) has been traditionally considered as a pure disorder of peripheral nervous system, characterized by neuropathic pain and degeneration of small-diameter nerve fibers in the skin. Previous functional MRI studies revealed abnormal activations of pain networks, but the structural basis underlying such maladaptive functional alterations remains elusive. We applied diffusion tensor imaging (DTI) to explore the influences of SFN on brain microstructures. Forty-one pathology-proven SFN patients with reduced skin innervation were recruited. White matter connectivity with the thalamus as the seed was assessed using probabilistic tractography of DTI. SFN patients had reduced thalamic connectivity with the insular cortex and the sensorimotor areas including the postcentral and precentral gyri. Furthermore, the degree of skin nerve degeneration, measured by intraepidermal nerve fiber density (IENFd), was associated with the reduction of connectivity between the thalamus and pain-related areas according to different neuropathic pain phenotypes, specifically, the frontal, cingulate, motor, and limbic areas for burning, electrical shocks, tingling, mechanical allodynia, and numbness. Despite altered white matter connectivity, there was no change in white matter integrity assessed with fractional anisotropy. Our findings indicate that alterations in structural connectivity may serve as a biomarker of maladaptive brain plasticity that contributes to neuropathic pain after peripheral nerve degeneration.