Protectin (CD59) is a glycosyl-phosphatidylinositol-anchored cell membrane glycoprotein, ubiquitously expressed, though to a different extent, on benign and malignant cells. CD59 inhibits complement (C)-mediated lysis of target cells by preventing the formation of the membrane attack complex, in the terminal step of C-activation. Recent experimental evidence demonstrates that CD59 is the main restriction factor of C-mediated lysis of malignant cells of different histotype. Additionally, a soluble form of CD59, that retains its anchoring ability and functional properties, has been most recently identified in body fluids and in culture supernatants of different malignant cells. In view of its functional role, CD59 may protect neoplastic cells from C-mediated lysis, contributing to their escape from innate C-control and to tumor progression; additionally, the expression of CD59 by neoplastic cells may contribute to impair the therapeutic efficacy of C-activating monoclonal antibodies (mAb) directed to tumor-associated antigens. In the light of the functional role of CD59, this review focuses on the structural features, tissue distribution and regulation of the expression of CD59 in malignant tissues, and on the foreseeable application(s) of CD59 to improve the therapeutic efficacy of clinical approaches of humoral immunotherapy with C-activating mAb in human malignancies.