During experimental sepsis, excessive generation of the anaphylatoxin C5a and reduction of the corresponding C5a receptor (C5aR) on neutrophils have been shown to result in an impaired innate immune response. However, the regulation of C5aR on neutrophils during sepsis is still in the dark. To elucidate the mechanism involved in the sepsis-induced loss of C5aR, in vitro studies on isolated human neutrophils and translational studies on healthy volunteers (n = 30) and patients with septic shock (n = 60) were performed (after approval by the Independent Ethics Committee of the University of Ulm). The sera of patients with sepsis presented evidence of complement activation with significantly increased levels of C3a, C5a, and C5b-9. The corresponding decrease in hemolytic activity could distinguish survivors from non-survivors. Neutrophils from patients with septic shock exhibited a significant decrease in C5aR expression which inversely correlated with serum concentrations of C-reactive protein (CRP) and clinical outcome (30 d survival). Whereas various inflammatory mediators failed to significantly alter C5aR expression, in vitro exposure of normal neutrophils to CRP led to a dose- and time-dependent loss of C5aR expression. The data suggest that septic shock in humans is associated with extensive complement activation and a CRP-dependent loss of C5aR on neutrophils. The expression level of C5aR on neutrophils may also be helpful in "immune monitoring" of patients in an advanced stage of sepsis.