Vaccinia replication is complex, as it involves both producing new infectious particles as well as a myriad of proteins dedicated to combating the host’s immune response. Although these proteins are often called “non-essential”, they are frequently needed for the virus to achieve maximum virulence in vivo. Two of these proteins are the vaccinia complement control protein (VCP) and A56, the vaccinia hemagglutinin. VCP had been previously described as a virulence factor that was secreted from infected cells and blocked the activation of the complement cascade; A56 was known to bind another viral protein, K2. We have found that VCP and A56 interact on the surface of infected cells, and that this interaction is important for full vaccinia virulence in vivo. The first part of this thesis focuses on showing a direct interaction between A56 and VCP on the surface of infected cells, and that the N-terminal cysteine of VCP is needed for this interaction. The next section establishes that this interaction occurs via an intermolecular disulfide bridge between the two proteins in a transfection model, and also extends this phenomenon to VCP homologs from other poxviruses. Mutagenesis shows that VCP binds to the 3rd cysteine (residue 162) of the ectodomain of A56. We also begin to show that viruses that cannot form the A56/VCP complex are attenuated in vivo, using a virus V where the N-terminal cysteine of VCP is mutated. In the last section, we create a virus with a recombinant A56 protein that cannot bind VCP. We show that this virus is attenuated in intranasal and intradermal models of infection in mice; infections done in C3-knockout mice suggest that this attenuation is complement dependent. This work shows that VCP is not only important as a secreted protein, and that the A56/VCP complex is important for the virus to achieve maximum pathogenesis in vivo. These results also provide insight into the contributions of the A56 protein to vaccinia virulence in an infection, and for the first time tests a site-directed A56 mutant in vivo.