Severe injury may lead to immunosuppression, multiple organ failure, and death. The aim of the study was to investigate the direct impact of soft tissue destruction on the development of trauma-associated immunomodulation. Hip surgery was considered to represent an isolated soft tissue trauma that allowed for the examination of changes taking place locally at the site of trauma or systemically with regard to monocyte function and leukocyte redistribution. Peripheral blood and wound fluid collected from the drains of 21 patients after hip surgery were analyzed to determine the cellular composition and/or the responsiveness of mononuclear cells (MNCs) to lipopolysaccharide (LPS). Different factors present in the wound fluids were tested for their capacity to modulate the MNC of healthy individuals with regard to cytokine and chemokine secretion. We found that various factors, including heat-shock protein (HSP) 60 and HSP70, were locally released at the site of soft tissue trauma and could be detected in wound fluids. The wound fluid-derived MNC (but not the peripheral blood-derived MNC) showed an impaired capacity to release TNF-alpha after LPS stimulation. Cell-free wound fluid suppressed in healthy individuals the LPS-induced TNF-alpha secretion by MNC. After surgery, granulocytosis was found in peripheral blood and in wound fluids, but monocytopenia was restricted to wound fluids. In parallel, wound fluids induced in healthy individuals the release by MNC of distinct chemokines specific for granulocytes and monocytes. These wound fluid-mediated effects of TNF-alpha suppression and chemokine induction could be mimicked by recombinant human HSP70 and, in part, by HSP60. Thus, tissue-derived factors, such as HSP70 released after injury, suppress monocyte function and, therefore, might favor the development of immunosuppression after severe injury.