Cytokines have been proposed as histamine-independent itch mediators. To investigate this hypothesis, single doses of interleukin-2 (IL-2, 10 MU/mL) and tumour necrosis factor alpha (TNF-alpha, 10 micrograms/mL) were delivered to the epidermis of 10 healthy volunteers with a controlled skin-prick model; 1% histamine and solvent controls were included in a double-blind, randomized crossover design. Itch ratings (computerized visual analogue scale) were obtained every 20 s for 15 min and cutaneous reactions (weal, flare and temperature) were measured. Reactions were also recorded after 2, 24 and 48 h. The mean itch ratings were: histamine 35.5, IL-2 3.3 (both P < 0.01 compared with control), TNF-alpha 1.6 and solvent control 1.75 (not significant). Weal and flare occurred only with histamine. In two volunteers, an inflammatory papule with transient pruritus developed 12-18 h after applying IL-2. In conclusion, IL-2 showed a rapid, low pruritogenic effect, which may be followed by an inflammatory response. TNF-alpha induced no itching in this setting. Skin-prick testing with appropriate doses of potential pruritogens provides a safe and sensitive model for further chemoreceptor studies.