The human retroviruses HTLV-I and HIV-I have previously been shown not to be lysed by human serum. An interaction between HIV and the complement system, however, has not been investigated in any detail. In this report we show that purified HIV as well as HIV-infected cells activate the complement system. In the case of virus-infected cells this activation is mediated by the alternative pathway of complement, whereas the classical pathway seems to be in operation for the triggering of the complement system by purified virus and recombinant envelope glycoprotein (gp 160). We demonstrate that this leads to the deposition of C3b and/or C3bi on the surface of infected cells. But the HIV-infected cells are not lysed by human complement. C3 fragments deposited on the surface of HIV-infected cells are capable of mediating immune adherence to complement receptor-bearing cells, such as human erythrocytes and phagocytes. Whether this might have an influence on infectivity of HIV for certain cells bearing complement receptors has yet to be shown.