Abstract An increased number of activated platelets and platelet/leukocyte aggregates are found in patients with chronic inflammatory diseases including cardiovascular disease. Platelet/leukocyte aggregates are not only indicative of cardiovascular disease, but also play an important role in the initiation and progression of disease. The role that complement regulatory proteins properdin and factor H play in controlling the formation of platelet/granulocyte aggregates, as well as which factor H domains are essential for the interaction with platelets on which complement is activating remain unknown. Here, we have determined that (a) the C-terminus of factor H is critical for the ability of the protein to protect platelets from the alternative pathway of complement, (b) blocking of properdin function using an inhibitory antibody significantly reduces the formation of platelet/granulocyte aggregates, while adding properdin increases the formation of these aggregates in a dose-dependent manner, and (c) factor H controls the properdin-mediated formation of platelet/granulocyte aggregates. Our data support critical roles for properdin and the C-terminus of factor H in controlling the formation of platelet/granulocyte aggregates. These studies may contribute to the understanding of the pathophysiological mechanisms involved in the interaction between platelets and granulocytes in chronic inflammatory diseases.