Patients who survive the initial phase after severe injury are predisposed to develop nosocomial infections. Such infectious complications may lead to sepsis, a life-threatening, mostly bacterial, systemic infection. The present study aimed to give further insight into the underlying pathophysiology predisposing for infectious complications after severe injury. Natural killer (NK) cells belong to the innate immune system and play a pivotal role in early pathogen clearance. This study focused on the CD56bright NK cells subset that is a main producer of the immune regulatory cytokine interferon (IFN)-gamma. Monocyte-derived interleukin (IL)-12 is the most potent inductor of CD56bright NK cell IFN-gamma production. Blood samples were taken of 10 severely injured patients presenting with an Injury Severity Score of 16 and above on consecutive days following the incident. Peripheral blood mononuclear cells were isolated and cultured in the presence of inactivated Staphylococcus aureus. The CD56bright NK cell-derived IFN-gamma production was severely impaired after trauma. Supplementation with IL-12 could only partly restore the IFN-gamma production. The NK cell suppression as well as the inability to respond to IL-12 were most pronounced on day 8 after trauma. Supplementation of IL-2 enhanced the IFN-gamma production from NK cells early after trauma while neutralization of IL-10 failed to do so. Analyses of the IL-12 signalling pathway revealed and impaired expression of the IL-12 receptor beta2 (IL-12Rbeta2) subunit as well as an impaired ability for signal transducer and activator of transcription (STAT) 4 phosphorylation. Both effects were most pronounced on day 8 following the incidence. Except for cells obtained on day 8 after trauma, the impaired CD56bright NK cell IFN-gamma production, IL-12Rbeta2 subunit expression, and STAT4 phosphorylation were at least partly restored when the cells were cultured in the absence of the trauma patient serum. Serum from trauma patients obtained on day 8 exerted a suppressive effect on NK cells from healthy controls. In summary, cell-intrinsic and cell-extrinsic suppression of CD56bright NK cells is maximal on day 8 after trauma. This coincides with the peak of infectious complications of trauma patients. An impaired NK cell function might contribute to the development of immune depression after severe trauma and the restoration of NK cell function after injury might represent a novel therapeutic target to prevent nosocomial infections and accompanied complications after severe injury.