Two chimeric monoclonal antibodies (mAb), cMOV18 and cMOV19, recognizing distinct epitopes of folate receptor highly expressed on epithelial ovarian cancer (EOC) cells were analyzed for their ability to activate complement (C) as a means to enhance their antitumor activity. The individual cMOVs failed to activate C on six EOC cell lines as documented by the marginal deposition of C components and the negligible C-dependent cytotoxicity (CDC). Conversely, the mixture of cMOVs was more effective, although the percentage of cell killing did not exceed 25%. Fluorescence-activated cell sorting analysis of EOC cells for surface expression of the membrane C regulatory proteins (mCRP) revealed high levels of CD46, variable expression of CD59, and absence of CD55. This finding was confirmed in tumor tissue specimens obtained from advanced-stage EOC patients and analyzed for the expression of mCRPs mRNA using a cDNA microarray and for the presence of proteins by immunohistochemistry. Incubation of EOC cells with neutralizing mAbs to CD46 and CD59 led to a significant increase in the CDC from 10%-20% to 45%-50%. The relative contribution of antibody-dependent cell cytoxicity (ADCC) and C-dependent killing of two EOC cell lines induced by the mixture of cMOV18 and cMOV19 was about 15% and 25%-35%, respectively, bringing the total killing to about 40%-50%. This value increased to 60%-70% after neutralization of CD46 and CD59 without an appreciable change of ADCC. These results suggest that C is the major contributor to the killing of EOC cells induced by the mixture of cMOV18 and cMOV19.