The classical pathway of complement is activated in various diseases. A main inhibitor of this pathway is the serpin C1-inhibitor (C1-Inh), which regulates activation at the level of C1. C1-Inh also inhibits the mannan binding lectin (MBL) associated serine proteinases−1 and −2. A deficiency of C1-Inh can result from a heterozygous genetic defect and is associated with a disease characterized by the occurrence of bouts of angio-edema (hereditary angioedema or HAE). A deficiency of C1-Inh can also be acquired (AAE) because of enhanced consumption of C1-Inh. AAE is often associated with underlying diseases, in particular, B-cell malignancies. A diagnosis of C1-Inh deficiency can be made by analysis of plasma levels of functional C1-Inh. HAE and AAE can be treated amongst others by substitution with C1 -Inh purified from pooled plasma from healthy blood donors. Animal studies and preliminary clinical studies suggest that C1-Inh also may be used for the treatment of various other diseases. In this chapter, we will briefly review the biochemistry and biology of C1-Inh. In addition, we will describe the methods used to evaluate the antigenic and functional state of C1-Inh.