Protein-based smallpox vaccines have shown to be effective alternatives to live virus vaccines in animal model challenge studies. It is believed that subunit vaccine protection is mainly mediated through the generation of antibodies. We, and others, have shown that Th1-type antibody responses are important for protection against poxvirus infections. This finding suggests that antibody-mediated protection by a protein-based smallpox vaccine may involve antibody that can fix complement and/or activate Fc receptors. Vaccinia virus, the prototype member of the poxvirus family, produces two infectious forms of virus: mature virus (MV) and extracellular virus (EV). EV is relatively resistant to neutralization by antibody, yet antibody against EV has been shown to protective in vivo. Therefore, we examined the importance of complement and Fc receptors in the protection afforded by antibody against EV. In the first part of this thesis, we found that polyclonal antibody against the EV proteins A33 and B5 can fix complement to efficiently neutralize EV in vitro. Additionally, we found that the complement activation requirements necessary for neutralization differ depending on the EV protein target used. We attribute these differences to the amount of A33 and B5 protein found on the EV outer membrane. We then show that in mice, both complement and Fc receptors are important for protection mediated by polyclonal antibody against the EV protein B5. In the last section, we found that non-human primates are better protected from monkeypox virus challenge by protein vaccination when the vaccine formulation generates more Th1-like antibody responses. Individual non-human primates receiving this vaccine had more homogeneous antibody responses that could neutralize EV in the presence of complement. Together, these studies implicate an important role for complement and Fc receptors in the protection by antibody against the EV form of poxviruses. This work highlights the importance of analyzing the mechanisms by which antibody provides protection from viral infection so that antibody-based vaccines and therapeutics can be more efficiently designed.