Novel immunological epitopes upon glyoxidation modified proteins have been discovered and multi-specific natural antibodies against them have been identified.  The association of glyoxidation with cancer has also been reported. We have probed the link of glyoxidation of histone H2A with autoimmune response in cancer. We report the formation of thermo stable amorphous aggregate formation in histone H2A upon methylglyoxal modification using circular dichroism (CD) analysis and transmission electron microscopy. The modified histone was found to be highly immunogenic that generates specific immune response in rabbits as analysed by cross reaction studies by competitive ELISA and Western blotting technique. The anti-methylglyoxal modified H2A antibodies were found in the circulating autoantibodies in various types of cancer patients by immunosorbant assay and gel retardation studies. The results clearly indicate the formation of highly specific antibodies in cancer patients against glyoxidation modified histone H2A with cross reactive tendencies with other glycated proteins and nucleic acids. The results are important because a link between AGE-RAGE axis (Advanced glycation end products and Receptors for AGEs) and carcinogenesis is emerging and the role of glyoxidation of proteins is expected in the development of biomarkers for the early detection of cancer.