Study Objectives: Vigilance is affected by induced and spontaneous skin temperature fluctuations. Whereas sleep deprivation strongly affects vigilance, no previous study examined in detail its effect on human skin temperature fluctuations and their association with vigilance. Design: In a repeated-measures constant routine design, skin temperatures were assessed continuously from 14 locations while performance was assessed using a reaction time task, including eyes-open video monitoring, performed five times a day for 2 days, after a normal sleep or sleep deprivation night. Setting: Participants were seated in a dimly lit, temperature-controlled laboratory. Patients or Participants: Eight healthy young adults (five males, age 22.0 ± 1.8 yr (mean ± standard deviation)). Intervention: One night of sleep deprivation. Measurements and Results: Mixed-effect regression models were used to evaluate the effect of sleep deprivation on skin temperature gradients of the upper (ear-mastoid), middle (hand-arm), and lower (foot-leg) body, and on the association between fluctuations in performance and in temperature gradients. Sleep deprivation induced a marked dissociation of thermoregulatory skin temperature gradients, indicative of attenuated heat loss from the hands co-occurring with enhanced heat loss from the feet. Sleep deprivation moreover attenuated the association between fluctuations in performance and temperature gradients; the association was best preserved for the upper body gradient. Conclusions: Sleep deprivation disrupts coordination of fluctuations in thermoregulatory skin temperature gradients. The dissociation of middle and lower body temperature gradients may therefore be evaluated as a marker for sleep debt, and the upper body gradient as a possible aid in vigilance assessment when sleep debt is unknown. Importantly, our findings suggest that sleep deprivation affects the coordination between skin blood flow fluctuations and the baroreceptor-mediated cardiovascular regulation that prevents venous pooling of blood in the lower limbs when there is the orthostatic challenge of an upright posture.