Evaluation of nerve fibers in the skin provides a useful tool for the diagnosis of small fiber neuropathies (SFNs). Our aim was to determine whether mitochondria are involved in SFN, indicating early axonal damage. We quantified mitochondrial respiratory chain complex IV (OXPHOS) and axonal (PGP 9.5) fluorescence on skin sections from 32 SFN patients and 14 healthy controls. Also, a group of six patients were recruited before and after 30‐day treatment with the mitotoxic antibiotic linezolid. We measured the co‐localization of OXPHOS within the intraepidermal and subpapillary dermal axons (PGP‐immunoreactive [PGP‐ir]). SFN patients with relatively preserved intraepidermal nerve fibers (SFN borderline) showed statistically significant reduction of OXPHOS (50.5 ± 33.9 µm² vs. 107.6 ± 81 µm² in controls, p < 0.02). A positive correlation was found between both PGP‐ir and OXPHOS in controls (Pearson's coefficient r = 0.59, p < 0.001), whereas such correlation was absent in SFN. With respect to baseline measurements, linezolid therapy increased both PGP‐ir and OXPHOS, which could be considered an initial compensatory toxic‐induced response. This study set out to identify a possible marker of axonal pre‐degenerative state in SFN borderline patients.