Neointima formation after vascular injury is exaggerated in ovariectomized (OVX) human C-reactive protein transgenic mice (CRPtg) compared to nontransgenic mice (NTG). We tested the hypothesis that this CRP-mediated exacerbation requires IgG Fc receptors (FcγRs). OVX NTG, CRPtg, and CRPtg lacking FcγRI, FcγRIIb, FcγRIII, or the common γ chain (FcRγ) had their common carotid artery ligated. Twenty-eight days later neointimal thickening in CRPtg/FcγRI-/- and CRPtg/FcRγ-/- was significantly less than in CRPtg and no worse than in NTG, whereas in CRPtg/FcγRIIb-/- and CRPtg/FcγRIII-/- neointimal thickness was equal to or greater than in CRPtg. Immunohistochemistry revealed human CRP in the neointima of CRPtg, but little or none was observed in those lacking FcγRI or FcRγ. Real-time reverse transcriptase-polymerase chain reaction demonstrated that FcγR types I to III were expressed in the CRPtg arteries, with FcγRI expression increasing by threefold after ligation injury. Levels of serum complement (C3), neointimal deposition of complement (C3d), and cellular composition (monocytes, macrophages, lymphocytes) in the neointima did not differ among the different CRPtg genotypes. However, by immunofluorescence a neointimal population of F4/80+CRP+ cells was revealed only in OVX CRPtg. The exaggerated response to vascular injury provoked by CRP in OVX CRPtg depends on FcγRI and probably requires its expression by F4/80+ cells. Copyright © American Society for Investigative Pathology.