Full expression of reflex cutaneous vasodilation is dependent on cyclooxygenase- (COX) and nitric oxide synthase- (NOS) dependent mechanisms. Low-dose aspirin therapy is widely prescribed to inhibit COX-1 in platelets for atherothrombotic prevention. We hypothesized that chronic COX inhibition with daily low-dose aspirin therapy (81mg) would attenuate reflex vasodilation in healthy human skin. Two microdialysis fibers were placed in forearm skin of 7 middle-aged (57±3 years) normotensive healthy humans with no preexisting cardiovascular disease taking daily low-dose aspirin therapy ( aspirin: 81mg) and 7 unmedicated healthy age-matched control (no aspirin: 55±3 years) subjects, one site serving as a control (Ringers) and the other NOS inhibited (NOS-inhibited: 10mM N^G nitro L-arginine methyl ester). Red cell flux was measured over each site by laser-Doppler flowmetry as reflex vasodilation was induced by increasing core temperature (T_or) 1.0°C using a water-perfused suit. Cutaneous vascular conductance was calculated (CVC=flux/MAP) and normalized to maximal CVC (CVC_max; 28mM SNP). CVC_max was not affected by either aspirin or NOS inhibition. The plateau in cutaneous vasodilation during heating (T_or=1.0°C) was significantly attenuated in the aspirin group ( aspirin: 25±3 vs. no aspirin: 50±7% CVC_max, p<0.001 between groups). NOS inhibition significantly attenuated %CVC_max in bothgroups ( aspirin: 17±2%CVC_max, no aspirin: 23±3%CVC_max; p<0.001 vs. control), but this attenuation was less in the no aspirin treatment group (p<0.001). This is the first observation that chronic low-dose aspirin therapy attenuates reflex cutaneous vasodilation through both COX- and NOS-dependent mechanisms.