Several polypeptides are secreted into the medium of cells infected with vaccinia virus, a cytoplasmic DNA virus belonging to the poxvirus family. One of these, a polypeptide of relative molecular mass 19,000 is structurally related to epidermal growth factor and binds to epidermal growth factor receptor stimulating proliferation of uninfected cells in vitro and in vivo. Here, we show that a second, and much more abundant secretory polypeptide, is also encoded by vaccinia virus and is structurally related to the superfamily of complement control proteins. Members of this family can block complement-mediated induction of the inflammatory response, and engulfment, killing and lysis of bacteria and viruses.