The intracellular killing of Staphylococcus aureus by human monocytes requires continuous stimulation by extracellular serum factors interacting with the cells via membrane binding sites. At least 75% of the intracellular killing in the presence of fresh serum was accounted for by the combined stimulatory activities of IgG, C3/C3b, and B/Bb. C3b is a more potent stimulator than C3, and Bb stimulates the killing to the same degree as B. The stimulation of intracellular killing by C3 and C3b occurs by interaction of the stable binding site of this molecule with the C3b receptor in the monocyte membrane. The stimulation of intracellular killing by B and Bb is most probably mediated via a binding site on these proteins interacting with a receptor site in the monocyte membrane. Both complement receptors, i.e., for C3b and B, are pronase sensitive. However, only the C3b receptor can be inhibited by (Fab')2 fragments of anti-C3 receptor antibodies, indicating that the binding sites for C3/C3b and B/bb are different.