The precise mechanism(s) underlying the thermal hyperemic response to local heating of human skin are not fully understood. The purpose of this study was to investigate a potential role for H1 and H2 histamine receptor activation in this response. Two groups of six subjects participated in two separate protocols and were instrumented with 3 microdialysis fibers on the ventral forearm. In both protocols, sites were randomly assigned to receive one of three treatments. In protocol 1, sites received 1) 500µM pyrilamine maleate (H1 receptor antagonist); 2) 10mM L-NAME to inhibit nitric oxide synthase; and 3) 500µM pyrilamine with 10mM L-NAME. In protocol 2, sites received 1) 2mM cimetidine (H2 antagonist); 2) 10mM L-NAME; and 3) 2mM cimetidine with 10mM L-NAME. A fourth site served as a control site (no microdialysis fiber). Skin sites were locally heated from a baseline of 33°C to 42°C at a rate of 0.5°C/5 seconds and skin blood flow was monitored using laser-Doppler flowmetry (LDF). Cutaneous vascular conductance (CVC) was calculated as LDF/MAP. To normalize skin blood flow to maximal vasodilation, microdialysis sites were perfused with 28mM sodium nitroprusside and control sites were heated to 43°C. In both H1 and H2 antagonist studies, no differences in initial peak or secondary plateau phase were observed between control and histamine receptor antagonist only sites or between L-NAME and L-NAME with histamine receptor antagonist. There were no differences in nadir response between L-NAME and L-NAME with histamine receptor antagonist. However, the nadir response in H1 antagonist sites was significantly reduced compared to control sites, but there was no effect of H2 antagonist on the nadir response. These data suggest only a modest role H1 and H2 receptors in local heating of human skin 3 for H1 receptor activation in the cutaneous response to local heating as evidenced by a diminished nadir response and no role for H2 receptor activation.