The plasma protein serum amyloid P (SAP) reduces neutrophil adhesion, inhibits the differentiation of monocytes into fibroblast-like cells called fibrocytes, and promotes phagocytosis of cell debris by macrophages. Together, these effects of SAP reduce key aspects of inflammation and fibrosis, and SAP injections improve lung function in pulmonary fibrosis patients. SAP functions are mediated, in part, by FcgammaRs, but the contribution of each FcgammaR is not fully understood. We found that aa Q55 and E126 in human SAP affect human fibrocyte differentiation and SAP binding to FcgammaRI. E126, K130, and Q128 affect neutrophil adhesion and SAP affinity for FcgammaRIIa. Q128 also affects phagocytosis by macrophages and SAP affinity for FcgammaRI. All the identified functionally significant amino acids in SAP form a binding site that is distinct from the previously described SAP-FcgammaRIIa binding site. Blocking FcgammaRI with an IgG-blocking Ab reduces the SAP effect on fibrocyte differentiation, and ligating FcgammaRIIa with Abs reduces neutrophil adhesion. Together, these results suggest that SAP binds to FcgammaRI on monocytes to inhibit fibrocyte differentiation, and binds to FcgammaRIIa on neutrophils to reduce neutrophil adhesion.