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Small fiber neuropathy (SFN) is a subtype of sensory neuropathy with acral pain and normal findings in routine nerve conduction studies.Twenty-four patients with SFN and matched controls were prospectively studied in this case-control study. Patients were assessed clinically, with standardized pain and depression questionnaires, by neurophysiologic tests, and by quantitative sensory testing. All patients underwent skin punch biopsy in a clinically affected (distal calf) and a nonaffected area (proximal thigh). Blood samples were collected for systemic cytokine gene expression analysis.Patients with SFN had a 2-fold higher gene expression for interleukin (IL)-2 (p < 0.0001), IL-10 (p = 0.01), and transforming growth factor-β1 (p = 0.001) in peripheral blood. Skin samples from affected areas showed increased IL-6 (7-fold; p = 0.001) and IL-8 (5-fold; p = 0.002) gene expression when compared to healthy controls. In 10/24 patients, SFN was termed length-dependent (LD) because of a ≥5-fold higher intraepidermal nerve fiber density in the proximal than in the distal skin. Patients with LD-SFN had higher gene expression in the affected distal skin than in nonaffected skin for tumor necrosis factor-α (2.6-fold; p = 0.04), IL-1β (2-fold; p = 0.02), IL-6 (>200-fold; p = 0.01), and IL-8 (>500-fold; p = 0.046). Inflammatory cells were present in most SFN samples but their numbers were not correlated with cytokine levels.Elevated local proinflammatory cytokines may be involved in the pathophysiology of pain in length-dependent small fiber neuropathy. These findings suggest a potential therapeutic role of locally applied cytokine inhibitors.