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Sleep disturbance, measured by either subjective report or electroencephalographic (EEG) assessment of sleep, correlates with a reduction of natural killer (NK) cell activity in major depression. To test whether sleep loss independent of mood disturbance alters daytime values of cellular immune function, the effect of late-night partial sleep deprivation on NK cell activity was studied in 23 medically and psychiatrically healthy male volunteers. After a night of sleep deprivation between 3 and 7 AM, NK cell activity was reduced in 18 of the 23 subjects with average lytic activity reduced significantly (p < .01) to a level 72% of the mean of three separate baseline values. After a night of resumed nocturnal sleep, NK cell activity had returned to baseline levels. These data implicate sleep in the modulation of natural immunity and demonstrate that even modest disturbances of sleep produce a reduction of NK cell activity.