Malignant transformation of ovarian cells of surface epithelial origin is associated with expression of a membrane-spanning glycoprotein, cancer antigen (CA)-125. The bulk of the putative CA-125 molecule is comprised a very large, folded, multivalent, mucin-like exodomain. That the extracellular motif of CA-125 exerts immunosuppressive effects which promote tumor progression has been suggested. We report that CA-125 attenuates complement lysis of antibody-sensitized cells. The secreted form of CA-125 derived from culture medium of the human ovarian adenocarcinoma cell line OVCAR-3 caused a dose-response inhibition of sheep erythrocyte hemolysis. Moreover, OVCAR-3 cells became prone to complement attack (trypan blue uptake) mediated by a gonadotropin-releasing hormone receptor antibody when (membrane-bound) CA-125 was excised/removed by trypsin/washing; this effect was counteracted by replacement with (soluble) CA-125. It is conceivable that CA-125 entraps/sheds effectors of the complement cascade.