Immune-mediated hemolytic anemia (IMHA) is a common disease that affects all breeds of dogs and is associated with significant morbidity and mortality. The intravascular hemolysis of erythrocytes in IMHA is caused by activation of the complement system, and is frequently fatal. There are currently no treatments that target complement activation in canine IMHA, however. Immunosuppressive drugs are the current standard treatment therapy, but have several drawbacks including delayed onset to effect, substantial inter-individual variation in response, and significant side effects. We have exciting preliminary data showing that the human C1 esterase (C1-INH), the only protein inhibitor of complement activation, abolishes canine complement-mediated hemolysis in-vitro. Ruconest® is an FDA licensed formulation of C1-INH already established to be safe to administer to dogs, but the biological efficacy of Ruconest® for inhibition of canine complement at established safe doses is not known at this time. Furthermore, pharmacokinetic data essential for recommending a dosing regimen are lacking. We will directly address both these critical gaps in our knowledge. C1-INH is a glycosylated protein, and therefore may elicit a delayed immune response that is not evaluated in routine safety assessments. Therefore, we will also determine if Ruconest® administration induces antibody formation or elicits an inflammatory cytokine response in dogs. Our goal is to generate the necessary data to progress this novel and exciting targeted approach to IMHA from the human to canine realm as quickly and safely as possible, and our proposed studies will allow us to do so.