To elucidate the effect of capsaicin-sensitive nerve fibers, which are known to contain substance P (SP) and other sensory neuropeptides, on the sneezing reflex, we have investigated the effect of capsaicin on this reflex provoked in guinea pigs passively sensitized with anaphylactic antibody followed by specific antigen challenge. It has already been established that histamine released from mast cells is a reliable inducer of the sneezing reflex in type I allergy. Our experimental results indicated that the frequency of sneezing provoked by antigen challenge as well as histamine application was significantly reduced by pre-treatment with capsaicin in a dose-dependent fashion. SP is considered to be one of the main neurotransmitters in sensory nerves. When the amount of SP in animal nasal mucosa was measured 12 h after capsaicin treatment, a marked reduction was noted. However, the histamine content in the nasal mucosa was not changed by capsaicin treatment. These data suggest that neuropeptides, especially SP, which are released or depleted from sensory nerves by capsaicin treatment, probably play an important role as neurotransmitters of the stimulant histamine in the development of sneezing in type I allergy.