Neutrophil hyperactivity contributes to organ failure whereas hypofunction permits sepsis. The chemokine receptors CXCR1 and CXCR2 are central to PMN function. We prospectively assessed CXCR function and expression in neutrophils (PMN) from trauma patients at high risk for pneumonia and their matched volunteers. CXCR2 specific calcium flux and chemotaxis were desensitized by injury, returning toward normal after 1 week. CXCR1 responses were relatively maintained. These defects appeared to be due to preferential suppression of CXCR2 surface expression. To evaluate potential mechanisms of in-vivo chemokine receptor regulation further we studied cross-desensitization of chemokines receptors in normal PMN. Susceptibility to desensitization was in the order CXCR2 >CXCR1 >fMLP/C5a. Trauma desensitizes CXC-receptors with CXCR2 especially vulnerable. Desensitization is most marked immediately post-injury, generally resolving by Day 7. High affinity chemoattractant receptors responsible for PMN chemotaxis from bloodstream to tissue appear to be regulated by injury. Receptors for end-target chemoattractants regulate CXCR1 and CXCR2 but resist suppression themselves and respond normally after injury. CXCR2 desensitization occurs prior to pneumonia, which developed in 44% of patients. Suppression of high-affinity PMN receptors like CXCR2 may predispose to pneumonia after trauma or other inflammatory conditions that lead to SIRS.