Recognition by the leukocyte integrins ?X?2 and ?M?2 of complement iC3b-opsonized targets is essential for effector functions including phagocytosis. The integrin-binding sites on iC3b remain incompletely characterized. Here, we describe negative-stain electron microscopy and biochemical studies of ?X?2 and ?M?2 in complex with iC3b. Despite high homology, the two integrins bind iC3b at multiple distinct sites. ?X?2 uses the ?X ?I domain to bind iC3b on its C3c moiety at one of two sites: a major site at the interface between macroglobulin (MG) 3 and MG4 domains, and a less frequently used site near the C345C domain. In contrast, ?M?2 uses its ?I domain to bind iC3b at the thioester domain and simultaneously interacts through a region near the ?M ?-propeller and ?2 ?I domain with a region of the C3c moiety near the C345C domain. Remarkably, there is no overlap between the primary binding site of ?X?2 and the binding site of ?M?2 on iC3b. Distinctive binding sites on iC3b by integrins ?X?2 and ?M?2 may be biologically beneficial for leukocytes to more efficiently capture opsonized pathogens and to avoid subversion by pathogen factors.