Abstract Human C-reactive protein (CRP) is an acute phase protein that binds to receptors on human and mouse leukocytes. We have recently determined that the high and low affinity receptors for CRP on human leukocytes are FcγRIIa and FcγRI, respectively. Previous work by others suggested that CRP receptors on mouse macrophages are distinct from FcγR. We have taken advantage of the availability of mice deficient in one or more FcγR to reexamine the role of FcγR in CRP binding to mouse leukocytes. Three strains of FcγR-deficient mice were examined: γ-chain-deficient mice that lack FcγRI and FcγRIII, FcγRII-deficient mice, and mice deficient in both γ-chain and FcγRII that lack all FcγR. No binding of CRP was detected to leukocytes from double-deficient mice, indicating that FcγR are required for CRP binding. CRP binding to leukocytes from γ-chain-deficient and FcγRII-deficient mice was reduced compared with binding to leukocytes from wild-type mice. Further analysis of CRP binding to macrophages, neutrophils, and lymphocytes provides direct evidence that FcγRIIb1, FcγRIIb2, and FcγRI are the receptors for CRP on mouse leukocytes. These findings may have important implications in understanding the physiological function of CRP.