Capsaicin, a neurotoxin which depletes substance P from primary afferent nerve fibres, was injected systematically into adult guinea pigs. The effects of capsaicin were studied by immunohistochemistry, electron microscopy and radioimmunoassay at times from 5 min to 1 year. Within 5 min after a single injection of capsaicin (50 mg/kg) substance P immunofluorescence appeared less intense and less homogeneous than normal (i.e. it appeared granular). Large nerve trunks remained evident, but there were fewer fine single nerve fibres. With increasing time there was a progressive decrease in the number of immunoreactive fibres; by 4 h there was a marked reduction in the number of fibres and by 24 h only an occasional fibre was evident. In animals sacrificed 2 or more hours after treatment large brightly fluorescent swellings were seen in many nerves. Depletion of substance P-immunoreactivity persisted for as long as 365 days after treatment. Electron microscopy revealed alterations in capsaicin-sensitive nerve fibres within 5 min after treatment. Many fibres appeared swollen and there was disruption of their internal morphology, e.g. loss of microtubules and filaments and presence of an amorphous flocculent material in the axons. With increasing time after treatment, electron-dense profiles, indicative of degenerating nerve fibres, were commonly seen associated with Schwann cells. These findings demonstrate that the effects of systemic administration of capsaicin to adult guinea pigs occur rapidly in capsaicin-sensitive nerve fibres. The long lasting depletion of substance P-containing fibres is due to their degeneration.