C-reactive protein (CRP) is an innate recognition molecule, which regulates immune responses by interaction with FcγR. CRP suppresses inflammation and autoimmunity in diverse experimental models. Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease in which platelets are cleared by splenic macrophages through FcγR. IVIG is used to treat human ITP. IVIG induces dendritic cells to transfer suppression of ITP (Siragam et al., 2006, Nat Med). In this study, splenocytes were treated with 200 μg/ml CRP or BSA or 1.8 mg/ml IVIG for 30 min, washed and transferred to naïve recipients. After 24 h, ITP was induced by injection of anti-CD41 mAb. Platelets were counted 24 h later. Anti-CD41 decreased platelet counts from 945±29 to 312±61 x 103/mm3. Platelet counts in recipients of 106 treated spleen cells were: BSA, 225±35; CRP, 672±25; and IVIG 590±35. Spleen cells from FcR γ-chain−/− or FcγRI−/− mice treated with CRP or IVIG were not protective and no protection was observed in FcγRIIb−/− mice. Macrophage depletion in vivo by Clodronate liposome treatment of the donor eliminated protection by CRP (363±9, p<0.001 vs CRP), but not IVIG (560±38). Thus, CRP treatment of spleen cells in vitro generates a cell that transfers suppression of ITP. Generation of this cell by CRP is dependent on FcγRI and macrophages. The findings allow for the characterization of the cells involved in the immunoregulatory properties of CRP.