In healthy humans, sleep deprivation (SD) has consistently been demonstrated to impair different parameters of the host defence system and of psychosocial functioning. However, the individual timing of these alterations and their possible association have remained unknown so far. We therefore investigated functional measures of the individual host defence system as well as of subjective well-being and psychosocial performance in 10 healthy male adults before and after SD, as well as after recovery sleep. In detail, we examined the number of leukocytes, granulocytes, monocytes, lymphocytes, B cells, T cells, T helper and cytotoxic T cells, natural killer (NK) cells as well as the interleukin-1 beta (IL-1 beta) release from platelets after serotonin (5-HT) stimulation. Mood and psychosocial performance (excitement, energy, ability to work and timidity) were measured by visual analogue scales. Taken together, SD induced a deterioration of both mood and ability to work, which was most prominent in the evening after SD, while the maximal alterations of the host defence system could be found twelve hours earlier, i.e., already in the morning following SD. Our findings therefore suggest an SD-induced alteration of these psychoimmune response patterns in healthy humans preceding deterioration of mood and psychosocial functioning.