BACKGROUND: Patients with post-COVID condition (PCC) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) experience symptoms potentially associated with small fiber neuropathy (SFN). METHODS: A sample of 90 participants, comprising 30 PCC patients, 30 ME/CFS patients, and 30 healthy controls (HC), matched by sex and age, was assessed. Neuropathic, autonomic, and fatigue symptoms were measured with TaskForce Monitor, the Sudoscan, heat and cold evoked potentials, In Vivo Corneal Confocal Microscopy (IVCCM), and specialized questionaries. RESULTS: PCC and ME/CFS patients demonstrated significantly higher levels of autonomic symptoms (H = 39.89, p <
0.001), neuropathic symptoms (H = 48.94, p <
0.001), and fatigue (H = 49.29, p <
0.001) compared to HC. Quantitative sensory testing revealed significant differences in heat detection thresholds between PCC patients and HC (F = 4.82
p <
0.01). Regarding corneal small fiber tortuosity, there were statistically significant differences between patients and HC (F = 6.80
p <
0.01), indicating pathological responses in patients. Small fiber tortuosity in IVCCM was identified as the main discriminator between patients and HC (AUC = 0.720
p <
0.01). CONCLUSION: PCC and ME/CFS patients demonstrated sensory SFN, as evidenced by impaired heat detection and increased tortuosity of small fibers in the central corneal subbasal plexus. The findings underscore the importance of a multimodal approach to comprehensively detect and characterize SFN. This study provides valuable scientific insights into the neuropathic manifestations associated with these conditions.