N-glycolylated (NeuGc) gangliosides are not naturally expressed in normal human tissues but are overexpressed in several tumors and have immunosuppressive capacity, contributing to cancer progression. The present work shows the existence of a natural antibody response against NeuGcGM3 in healthy donors. These antibodies specifically recognized NeuGcGM3 and killed tumor cells expressing the antigen by a complement mediated mechanism. Interestingly, even after complement inactivation 17% of the positive sera showed a direct cytotoxic effect over the tumor cells. This cytotoxicity was dependent on the presence of the antigen on the tumor cell and resembles an oncotic necrosis kind of cell death. The levels of anti-NeuGcGM3 antibodies in the sera of healthy donors and the percentage of donors with this natural immunity decreases with age. Furthermore we could not detect this reactivity in the sera of 51 non-small cell lung cancer (NSCLC) patients that matched in sex and age the assessed healthy donors. Interestingly the level of sera IgM, but not IgG, was significantly lower in cancer patients in comparison with healthy donors. Also, the capacity of patients B1 cells to spontaneously secrete IgM and to respond to DAMPs, like CpG, seems to be affected. Defects in the natural surveillance against tumor antigens could increase the risk of elderly donors to develop cancer and affect the capacity of cancer patients to effectively fight against them.