Evidence is presented that treatment with a selective inhibitor of the alternative complement pathway, sCR1[desLHR-A], protects the ex vivo perfused rabbit heart from human complement-mediated injury. Hearts from male New Zealand white rabbits were perfused in the Langendorff mode. After equilibration, normal human plasma was added to the perfusate as a source of complement. Concomitant with the addition of human plasma, vehicle (n = 13), soluble complement receptor type 1 (sCR1) (n = 10), or sCR1[desLHR-A], a truncated version of sCR1 that lacks the C4b binding region (n = 10) was included in the perfusate. Hemodynamic variables were obtained for all groups before (baseline) and after the addition of human plasma. Compared to vehicle-treated hearts, variables recorded during perfusion with human plasma including coronary perfusion pressure, left ventricular developed pressure, and left ventricular end diastolic pressure, along with a reduction of creatine kinase efflux, were improved in hearts perfused with either complement inhibitor. In addition, in vitro hemolysis assays were utilized to discriminate between the classical and alternative pathways. The addition of sCR1 to human serum prevented both the classical and alternative pathway-mediated hemolysis while sCR1[desLHR-A] prevented only the alternative pathway-mediated lysis. This study indicates that deletion of the C4b-binding site from sCR1 results in a new pharmacological moiety, sCR1[desLHR-A], that primarily inhibits the alternative pathway of human complement.