Macrophage fusion leading to the formation of multinucleated giant cells is a hallmark of chronic inflammation. Several membrane proteins have been implicated in mediating cell-cell attachment during fusion， but their binding partners remain unknown. Recently， we demonstrated that interleukin-4 (IL-4)-induced fusion of mouse macrophages depends on the integrin macrophage antigen 1 (Mac-1). Surprisingly， the genetic deficiency of intercellular adhesion molecule 1 (ICAM-1)， an established ligand of Mac-1， did not impair macrophage fusion， suggesting the involvement of other counter-receptors. Here， using various approaches， including signal regulatory protein α (SIRPα) knockdown， recombinant proteins， adhesion and fusion assays， biolayer interferometry， and peptide libraries， we show that SIRPα， which， similar to ICAM-1， belongs to the Ig superfamily and has previously been implicated in cell fusion， interacts with Mac-1. The following results support the conclusion that SIRPα is a ligand of Mac-1: () recombinant ectodomain of SIRPα supports adhesion of Mac-1-expressing cells; () Mac-1-SIRPα interaction is mediated through the ligand-binding αI-domain of Mac-1; () recognition of SIRPα by the αI-domain conforms to general principles governing binding of Mac-1 to many of its ligands; () SIRPα reportedly binds CD47; however， anti-CD47 function-blocking mAb produced only a limited inhibition of macrophage adhesion to SIRPα; and () co-culturing of SIRPα- and Mac-1-expressing HEK293 cells resulted in the formation of multinucleated cells. Taken together， these results identify SIRPα as a counter-receptor for Mac-1 and suggest that the Mac-1-SIRPα interaction may be involved in macrophage fusion.