Leukocyte-derived microparticles (MPs) are markers of cardiovascular diseases and contribute to pathogenesis by their interaction with various cell types. The presence and activation state of a multifunctional leukocyte receptor, integrin α_Mβ₂ (CD11b/18), on MPs derived from human neutrophils (PMNs) were examined. α_Mβ₂ expression was significantly enhanced on MPs derived from stimulated compared with resting PMNs. Furthermore, α_Mβ₂ on MPs from stimulated but not resting PMNs was in an activated conformation because it was capable of binding activation-specific monoclonal antibodies (CBRM1/5 and mAb24) and soluble fibrinogen. MPs expressing active α_Mβ₂ interacted with and were potent activators of resting platelets as assessed by induction of P-selectin expression and activation of α_IIbβ₃. With the use of function-blocking antibodies and MPs obtained from α_M^−/−-deficient mice, we found that engagement of GPIbα on platelets by α_Mβ₂ on MPs plays a pivotal role in MP binding. Platelet activation by MPs occurs by a pathway dependent on Akt phosphorylation. PSGL-1/P-selectin interaction also is involved in the conjugation of MPs to platelets, and the combination of blocking reagents to both α_Mβ₂/GPIbα and to PSGL-1/P-selectin completely abrogates MP-induced platelet activation. Thus, cooperation of these 2 receptor/counterreceptor systems regulates the prothrombotic properties of PMN-derived MPs.