Complement sensitization of red blood cells (RBCs) can cause life-threatening hemolytic anemias. We have previously shown that complement receptor I (CRI) derivatives specifically the N-terminal region with decay accelerating activity (DAA) for inactivation of a key enzyme in the complement cascade can reduce complement-mediated RBC destruction in vitro and in an in vivo mouse model of hemolytic transfusion reaction. In the present study, we have modeled the N-terminal CRI molecule based on the X-ray crystal structure of decay accelerating factor and the NMR structure of a homologous CRI domain. Based on the homology model, we identified a 34-mer peptide encompassing the putative DAA which in vitro reduced hemolysis, C3a release and surface C3 deposition. More importantly, this peptide at 0.6 mM was effective in prolonging survival of transfused incompatible RBCs in vivo. Our results indicate that CRI-based structure-function studies may provide insights for developing structure-derived transfusion therapeutics in the future. (c) 2006 Elsevier Inc. All rights reserved.