TRPM8 has previously been identified as a cold- and menthol- activated ion channel which gives rise to detection of cold sensation in the innocuous temperature range (Peier et al., 2002). Recently, their presence has been reported in rat pulmonary artery and aorta (Yang et al., 2006). We have recently shown that TRPM8 agonists raise intracellular calcium and cause contraction in isolated vascular smooth muscle cells (VSMCs) and relaxed segments from several rat arteries (Melanaphy et al., 2008), although vasodilatation is induced in precontracted arteries Melanaphy et al., 2007). In this study we have examined a possible role for TRPM8 channels in controlling cutaneous blood flow in humans. Following approval from the QUB Medical School Ethics Committee, forearm cutaneous red cell flux (cRCF) was measured by means of a laser Doppler probe in 10 healthy volunteers (5 male, 5 female) aged 21.0 ± 0.3 years (mean ± S.E.M.) during 30 minutes of passive application of menthol (3% in 25% ethanol vehicle) to the probe chamber. Before application of menthol, cRCF was relatively low (18 ± 2 flux units). After approximately 14 minutes (median 14, range 10 – 22 minutes) application of menthol, cRCF increased considerably in 9/10 subjects, so that cRCF had risen by 534 ± 138% (P<0.01, n=10, paired Student’s t-test, performed on raw data) above baseline after 30 minutes. No significant increase was seen with vehicle alone, applied concurrently. There were no significant differences between males and females in the effects of menthol. However, these dilator effects were markedly reduced by prior iontophoretic application of atropine (10 mM in sterile water, 1 x 30 seconds at 75 μA, 12 minutes prior to acetylcholine), or prior passive application of L-NAME (100 nM in sterile water, 30 minutes application), the inhibitor of nitric oxide production (250 ± 76 %, P<0.05 and 352 ± 59%, P=0.061, respectively). This study suggests that TRPM8 channels are active in control of human cutaneous blood vessels, causing vasodilatation of constricted vessels. Its effects may be mediated, in part, by production of nitric oxide. Additional details of this mechanism await further experimentation.