The human complement system plays an important role in the control of Staphylococcus aureus infection. For instance, we previously demonstrated that the central complement component deposited on the organism's surface, C3b, can be cleaved by the host complement control protein, factor I, resulting in diminished phagocytosis of S. aureus. In the present study, we have identified clumping factor A (ClfA) from cell wall proteins of S. aureus as a specific protein bound by factor I. Recombinant ClfA (rClfA) containing the full-length A region (peptides 40-559) also bound factor I. We identified an 50-kDa fragment of ClfA that is shed by S. aureus into growth medium. The shed ClfA fragment was derived from the A region of ClfA and bound factor I. rClfA and the shed ClfA fragment increased factor I cleavage of C3b into inactive C3b. Our findings describe a new S. aureus mechanism for modification of host complement activities.