Excessive daytime sleepiness (EDS) and fatigue are frequent symptoms in the general population and the chief complaint of the majority of patients at Sleep Disorders Centers. There is evidence that the inflammatory cytokines tumor necrosis factor-α (TNFα), interleukin-1β (IL-1β), and IL-6 are involved in physiological sleep regulation and that their administration to humans is associated with sleepiness and fatigue. To explore whether plasma levels of TNFα, IL-1β, and IL-6 are elevated in patients with EDS, we measured morning plasma levels of TNFα, IL-1β, and IL-6 in 12 sleep apneics, 11 narcoleptics, 8 idiopathic hypersomniacs, and 10 normal controls. TNFα was significantly elevated in sleep apneics and narcoleptics compared to that in normal controls (P< 0.001 and P = 0.001, respectively). Plasma IL-1β concentrations were not different between sleep disorder patients and controls, whereas IL-6 was markedly and significantly elevated in sleep apneics compared to that in normal controls (P = 0.028). The primary factor influencing TNFα values was the degree of nocturnal sleep disturbance, whereas the primary determinant for IL-6 levels was the body mass index. Our findings suggest that TNFα and IL-6 might play a significant role in mediating sleepiness and fatigue in disorders of EDS in humans.