Complement control proteins include a group of membrane-bound surface antigens that protect cells from complement lysis by preventing formation of the membrane attack complex (MAC) of complement. HIV-1 and SIV are known to possess cellular proteins, making it possible that some of them contribute to the ability of these viruses to evade complement lysis. Three complement control proteins, CD46 (membrane cofactor protein), CD55 (decay accelerating protein), and CD59 (HRF20), were found by flow cytometry to be expressed on the surface of CD4+ cell lines commonly used for HIV-1 and SIV synthesis. Monoclonal antibodies to each of these proteins precipitated HIV-1 IIIB and SIV delta/B670 synthesized in CEM x 174 cells and two primary HIV-1 isolates synthesized in peripheral blood mononuclear cells, indicating that CD46, CD55, and CD59 are physically associated with the virus membrane after the virus has been released from the surface of infected cells. Additional experiments showed that the precipitated material contained infectious virus, confirming that whole virus was precipitated. Evidence that CD46 and CD59 are immunogenic in macaques was found when anti-cell antibodies in plasmas from macaques immunized with human cell-grown SIV blocked anti-CD46 and anti-CD59 from binding to the surface of CEM x 174 cells. Anti-cell antibodies rendered HIV-1 susceptible to complement lysis as measured by the release of p24 core protein, and consistently produced a complement-dependent reduction in HIV-1 and SIV infectivity of 1-3 logs. These results demonstrate that CD46, CD55, and CD59 are common surface constituents of HIV-1 and SIV. The results also raise the possibility that the mechanism of SIV vaccine protection attributed to anti-cell antibodies could have involved complement-mediated virolysis.