Abstract Sleep loss has been associated with increased sleepiness, decreased performance, elevations in inflammatory cytokines, and insulin resistance. Daytime napping has been promoted as a countermeasure to sleep loss. To assess the effects of a 2-hour mid-afternoon nap following a night of sleep loss on post-nap sleepiness, performance, cortisol, and interleukin-6 (IL-6), 41 young healthy individuals (20 men, 21 women) participated in a 7-day sleep deprivation experiment (four consecutive nights followed by a night of sleep loss and two recovery nights). Half of the subjects were randomly assigned to take a mid-afternoon nap (1400-1600) the day following the night of total sleep loss. Serial 24-hour blood sampling, multiple sleep latency test (MSLT), subjective levels of sleepiness, and psychomotor vigilance task (PVT) were completed on the fourth (pre-deprivation) and sixth days (post-deprivation). During the nap, subjects had a significant drop in cortisol and IL-6 levels (P< 0.05), while after the nap, they experienced significantly less sleepiness (MSLT and subjective) (P< 0.05) and a smaller improvement on the PVT (P< 0.1). At this time, they had a significant transient increase in their cortisol levels (P< 0.05). In contrast, the levels of IL-6 tended to remain decreased for approximately eight hours (P = 0.1). We conclude that a 2-hour mid-afternoon nap improves alertness and to a lesser degree performance and reverses the effects of one night of sleep loss on cortisol and IL-6. The redistribution of cortisol secretion and the prolonged suppression of IL-6 secretion are beneficial, as they improve alertness and performance.