Recent evidence suggests a role for vasoactive intestinal polypeptide (VIP) in active vasodilatation and it has been shown that VIP-mediated vasodilatation includes a nitric oxide (NO) and histamine component. Thus, the purpose of this study was to determine the role of H1 and H2 histamine receptors and to examine a potential interaction between NO and histamine receptors in cutaneous active vasodilatation. Eleven subjects were instrumented with four microdialysis fibres. Site 1 served as a control and site 2 was perfused with l-NAME to inhibit nitric oxide synthase. Site 3 was perfused with either the H1 antagonist pyrilamine maleate or the H2 antagonist cimetidine. Site 4 was perfused with l-NAME plus pyrilamine maleate or l-NAME plus cimetidine. Laser-Doppler flowmetry (LDF) was used as an index of skin blood flow and cutaneous vascular conductance (CVC) was calculated as LDF/mean arterial pressure and normalized to maximal vasodilatation achieved via 28 mm sodium nitroprusside infusion. During whole body heating, subjects' sublingual temperature increased a minimum of 0.8°C. In the H1 antagonist studies, CVC in l-NAME, pyrilamine, and combined l-NAME plus pyrilamine sites was significantly reduced compared with control (P < 0.001). The l-NAME and combined l-NAME plus pyrilamine sites were significantly reduced compared with pyrilamine only sites (P < 0.05) but no significant differences were observed between sites. In the H2 receptor antagonist studies, CVC in control sites was not significantly different from cimetidine sites. There was no difference between the l-NAME and combined l-NAME plus cimetidine sites but these sites were significantly attenuated compared with control and cimetidine only sites (P < 0.05). These data suggest the rise in skin blood flow during whole body heating contains an H1 histamine receptor component but do not support an H2 histamine receptor component. Furthermore, part of the NO-dependent component of active vasodilatation can be explained by H1 receptor activation.