In this issue of Blood, Feng and coworkers present data suggesting a role for von Willebrand factor (VWF) in the proteolytic inactivation of complement C3b by factor I (CFI).1Whereas smaller VWF multimers, especially dimers, tetramers, and hexamers, enhance C3b inactivation by CFI, large and unusually large VWF multimers are devoid of this cofactor activity and, therefore, they enhance complement activation by the alternative pathway C3 convertase, C3bBb.