The functional properties of afferent fibres, especially C-fibres, have been studied over the 46 days following application of capsaicinoids to a segment of the saphenous nerve in the rat. After 1–3 days, approximately half of the C-afferents were found to be non-conducting at or immediately distal to the treatment site. By 6–9 days there was some recovery of conduction at the treatment site, but few of the conducting fibres were excitable from the skin. From 12 days onwards, C-fibre conduction in the segment of nerve both proximal and distal to the treatment site was reduced and of the conducting fibres relatively few had cutaneous receptive fields. In the sample of C-fibres with cutaneous receptive fields the proportion of polymodal nociceptors was reduced markedly compared with control values. Analysis of the numbers of surviving units shows a large effect on C-polymodal nociceptors, but no significant change in the numbers of any other type of afferent unit. At 2 weeks, when C-fibre numbers were reduced to about one third, there was a virtual abolition of antidromic vasodilatation and an 85% fall in skin substance P levels. The synthetic capsaicinoid, NE-21610, had similar actions to capsaicin and was more potent in depleting skin substance P levels. These results confirm that capsaicinoids produce a selective local lesion on nociceptive C-fibres in rat cutaneous nerves. In addition, the transient and partial nature of functional recovery indicates that capsaicin may also cause a longer-term toxic action that inhibits significant regeneration.