AIMS: Histamine, cowhage and capsaicin can be used to experimentally induce itch in humans. However, the quality of the sensations and the time courses of the itch intensity are different, suggesting that different classes of nerves are affected by the three substances. This study aimed to compare the perceptions evoked by those substances. METHODS: Native cowhage spicules as well as inactive spicules coated with histamine or capsaicin were inserted into the skin of the lower forearm of 30 subjects in double-blinded experiments. The subjects rated the intensity of burning and itch on a visual analogue scale (VAS) over a period of 7 minutes. Simultaneously, skin blood flow of the finger as a measure of vasoconstriction was recorded by laser Doppler flowmetry. The qualities of itch and burning were evaluated using a questionnaire with 24 adjectives. RESULTS: The intensities and time courses of itch were clearly different for the three substances: Histamine induced the strongest itch, followed by cowhage and capsaicin. There was no significant difference in the intensity of burning. During capsaicin the burning sensation dominated throughout the observation period. All three substances induced a vasoconstriction immediately after the stimulus application which slowly recovered. Histamine had the strongest, cowhage the weakest effect. After Capsaicin blood flow remained below baseline, while after histamine and cowhage blood flow recovered after 5 minutes. Itch and burning-related sensations showed highest ratings for histamine on the itching scale while capsaicin revealed highest ratings for pain related adjectives like burning, sharp, biting and painful. CONCLUSIONS: These findings suggest that the three substances induce different qualities of itch and activate different neuronal pathways.