The precise role of nitric oxide (NO) in cutaneous active vasodilatation in humans is unknown. We tested the hypothesis that NO is necessary to permit the action of an unknown vasodilator. Specifically, we investigated whether a low-dose infusion of exogenous NO, in the form of sodium nitroprusside (SNP), would fully restore vasodilatation in an area of skin in which endogenous NO was inhibited during hyperthermia. This finding would suggest a 'permissive' role for NO in active vasodilatation. Eight subjects were instrumented with three microdialysis fibres in forearm skin. Sites were randomly assigned to (1) Site A: control site; (2) Site B: NO synthase (NOS) inhibition during established hyperthermia; or (3) Site C: NOS inhibition throughout the protocol. Red blood cell flux was measured using laser-Doppler flowmetry (LDF) and cutaneous vascular conductance (CVC; LDF/mean arterial pressure) was normalized to maximal vasodilatation at each site. In Site B, NG-nitro-L-arginine methyl ester (L-NAME) infusion during hyperthermia reduced CVC by approximately 32 % (65 +/- 4 % CVCmax vs. 45 +/- 4 % CVCmax; P < 0.05). Vasodilatation was not restored to pre-NOS inhibition values in this site following low-dose SNP infusion (55 +/- 4 % CVCmax vs. 65 +/- 4 % CVCmax; P < 0.05). CVC remained significantly lower than the control site with low-dose SNP infusion in Site C (P < 0.05). The rise in CVC with low-dose SNP (deltaCVC) was significantly greater in Site B and Site C during hyperthermia compared to normothermia (P < 0.05). No difference in deltaCVC was observed between hyperthermia and normothermia in the control site (Site A). Thus, NO does not act permissively in cutaneous active vasodilatation in humans but may directly mediate vasodilatation and enhance the effect of an unknown active vasodilator.