Endogenous nerve growth factor (NGF) levels were studied in patients with nerve trauma, diabetes mellitus and leprosy, the most common causes of human peripheral neuropathy. In diabetics, there was an early length-dependent dysfunction of small-diameter sensory fibres, with depletion of skin NGF and the sensory neuropeptide substance P. The NGF depletion correlated significantly with decreased skin axon-reflex vasodilatation, which is mediated by small sensory fibres at least partly via substance P release. Immunostaining showed depletion of NGF in keratinocytes in diabetic skin. In injured nerves, NGF levels were reduced when compared to intact nerve, except acutely distal to injury; NGF-immunostaining was seen in Schwann cells in distal segments, including neuromas. NGF levels were decreased in leprosy-affected skin and nerve. The role of neurotrophins in the rational treatment of human neuropathies is discussed e.g. loss of nociception and axon-reflex vasodilatation contribute to skin ulceration, a major and serious complication, for which NGF may provide prophylaxis.