The effects of topical treatment with capsaicin or mustard oil on histamine-induced pruritus, wheal formation and flare response were studied in the human skin. Capsaicin pretreatment resulted in a reversible marked reduction or abolition of the axon reflex flare, but did not influence whealing. Itching was also strongly diminished or even abolished, provided that the flare response was completely blocked. The onset of itching was significantly promoted by pretreatment of the skin with mustard oil, inducing axon reflex vasodilatation. It is concluded that, in addition to the axon reflex flare, capsaicin-sensitive peptide-containing primary afferent neurones are also intimately involved in the mediation of the sensation of itching.