To study inherent differences in skin function related to regional variation, we tested the hypothesis that different reactivities of small blood vessels via their direct and indirect activation by histamine play an important role in the observed regional variation of processes. Histamine was administered to three cutaneous regions in 20 volunteers, and the induced response was quantified utilizing spectrophotometry and laser Doppler flowmetry. The back exhibited the greatest response, followed by the forearm and ankle in decreasing order of responsiveness. We suggest that the intensity of the wheal and flare response may partly be related to the local reactivity of the blood vessels once the histamine actually reached them, and to their indirect dilatation via the axonal reflex. These blood vessel response observations may provide initial insight into inherent functional differences influencing cutaneous manifestations of endogenous and exogenous diseases.