Background Idiopathic polyneuropathy is an asymmetrical, length-dependent neuropathy in which neurophysiology demonstrates axonal damage involving large fibers, along with insidious onset and slow progression over 6 months, with no identified etiology in spite of thorough investigations. This study aimed to evaluate the diagnostic role of clinical, electrophysiological, and histopathological studies in patients with idiopathic polyneuropathy. Methods Case–control study included 20 patients with clinical and neurophysiological evidence of sensory or sensory–motor neuropathy with no apparent etiology after laboratory investigation were recruited from 127 patients with sensory–motor neuropathy of unknown etiology (the patients group). Twenty apparently healthy individuals, age- and sex-matched, with no neuropathy symptoms (the control group), were recruited from the Neurology Clinic of Al-Azhar University, Assuit. Results Age of onset of patients with idiopathic polyneuropathy (44–70) years, duration of illness (1–6) years, 60% had painful neuropathy, diagnostic neuropathic pain questioner (DN4 score) (5–7), abnormal pin brick (80%), abnormal vibration (90%), abnormal fine touch (75%), distal weakness (70%), and lost ankle reflex (90%). In the control group, there were substantial differences with respect to prolonged latency, diminished sympathetic skin response amplitude, and significant intraepidermal nerve fiber density reduction in skin biopsy cases. In diagnosing idiopathic polyneuropathy, the specificity and sensitivity of sympathetic skin response were (80–86)% and (81–89.5)%, respectively, whereas those of diminished intraepidermal nerve fiber density were (92.5%) and (97.5%), respectively. Conclusion The assessment of intraepidermal nerve fiber density had an important good diagnostic role in cases presented with polyneuropathy.