Substance P (SP) is believed to be a major mediator of neurogenic inflammation. To determine whether the skin reactivity of SP is increased in asthmatics, we examined the reactivity to intradermal injections of SP, the C-terminal and N-terminal peptides SP6-11 and SP1-9, respectively, and neurokinin A (10(-7)-10(-5) M) in 12 asthmatics and 9 normal subjects. SP and the N-terminal peptide SP1-9 induced both erythemas and wheals in asthmatics and in normal subjects, whereas the C-terminal peptide SP6-11 and neurokinin A primarily induced only wheals in both groups. SP induced greater erythemas and wheals in asthmatics than in normal subjects. SP1-9 also induced greater erythemas and wheals in asthmatics than in normal subjects. However, the wheals induced by SP6-11 or neurokinin A were not significantly different in either group. Therefore, the increased skin reactivity to SP was the N-terminal peptide dependent, which has been shown to be able to activate skin mast cells. We conclude that the skin reactivity to SP is increased in asthmatics, possibly through the increased reactivity of skin mast cells.