Three children, from different kinships, with generalized insensitivity to pain, showed unusual manifestations of congenital, presumably inherited, sensory and autonomic neuropathy. The first child appeared to have a syndrome resembling those previously described as congenital indifference to pain, congenital universal loss of pain sensation from infancy without other apparent neurological deficit. Unlike most types of hereditary sensory and autonomic neuropathies (types I, II, III), but like type IV, she had normal sensory nerve action potentials. Abnormalities of sudomotor function and of somatosensory evoked potentials were demonstrated. A severe decrease in the number of sural nerve A delta fibres and a small reduction in C fibres were demonstrated morphometrically. An abnormality of C fibres was confirmed by a marked reduction in nerve dopamine-beta-hydroxylase activity. The plasma and CSF concentrations of beta endorphins, substance P and several other neuropeptides and hormones were normal. Unequivocal evidence of a neuropathic lesion is provided by this patient; her disorder may be identified as the fifth type of hereditary sensory and autonomic neuropathy. The second patient had a congenital pansensory neuropathy and progressive retinitis pigmentosa. Whether the disorder is inherited and, if so, whether the retinitis pigmentosa results from the same or from a second genetic abnormality, is unclear. The third case has, in addition to what is usually seen in hereditary sensory and autonomic neuropathy, type II, an unusually severe kinaesthetic difficulty in oral food handling. The sural nerves of the second and third patients had fibre composition characteristic of hereditary sensory and autonomic neuropathy, type II, few or no myelinated fibres and reduced numbers of unmyelinated fibres.