Prolonged and severe sleep deprivation is associated with alterations of natural and cellular immune function. To determine whether alterations of immune function also occur after even a modest loss of sleep, the effects of early‐night partial sleep deprivation on circulating numbers of white blood cells, natural killer (NK) cell number and cytotoxicity, lymphokine‐activated killer (LAK) cell number and activity, and stimulated interleukin‐2 (IL‐2) production were studied in 42 medically and psychiatrically healthy male volunteers. After a night of sleep deprivation between 10 P.M. and 3 A.M., a reduction of natural immune responses as measured by NK cell activity, NK activity per number of NK cells, LAK activity, and LAK activity per number of LAK precursors (CD 16, 56, CD25) was found. In addition, concanavalin A‐stimulated IL‐2 production was suppressed after sleep deprivation due to changes in both adherent and nonadherent cell populations. After a night of recovery sleep, NK activity returned to baseline levels and IL‐2 production remained suppressed. These data implicate sleep in the modulation of immunity and demonstrate that even a modest disturbance of sleep produces a reduction of natural immune responses and T cell cytokine production.—Irwin, T., McClintick, J., Costlow, C., Fortner, M., White, J., Gillin, J. C. Partial night sleep deprivation reduces natural killer and cellular immune responses in humans. FASEB J. 10, 643‐653 (1996)