In humans, the nocturnal fall in internal temperature is associated with increased endogenous melatonin and with a shift in the thermoregulatory control of skin blood flow (SkBF), suggesting a role for melatonin in the control of SkBF. The purpose of this study was to test whether daytime exogenous melatonin would shift control of SkBF to lower internal temperatures during heat stress, as is seen at night. Healthy male subjects (n=8) underwent body heating with melatonin administration (Mel) or without (Cont), in random order at least a week apart. SkBF was monitored at sites pretreated with bretylium (BT) to block vasoconstrictor nerve function and at untreated sites. Cutaneous vascular conductance (CVC), calculated from SkBF and arterial pressure, sweating rate (SR) and heart rate (HR) were monitored. Skin temperature was elevated to 38 °C for 35-50 min. Baseline esophageal temperature (Tes) was lower in Mel than in Cont (P0.01). The Tes threshold for cutaneous vasodilation and the slope of CVC with respect to Tes were also lower in Mel at both untreated and BT treated sites (P0.05). The Tes threshold for the onset of sweating and the Tes for a standard HR were reduced in Mel. The slope of the relationship of HR, but not SR, to Tes was lower in Mel (P0.05). These findings suggest that melatonin affects the thermoregulatory control of SkBF during hyperthermia via the cutaneous active vasodilator system. Since control of SR and HR are also modified, a central action of melatonin is suggested.