Methylglyoxal (MG) is formed in several metabolic pathways as products, which are highly toxic, and detoxified by glyoxalase enzyme system to lactate. It is a tricky molecule as it has dual role, on one hand its synthesis is increased in oxidative stress and on the other hand it is considered as inhibitor of cell cycle particularly in the rapidly proliferating cells. Considering these aspects of methylglyoxal, the current study was designed to establish the potential role of MG in patients exhibiting oral premalignant lesions and in patients with established malignant disease. The aim of the present study was to determine the serum methylglyoxal concentration in pa-tients with oral premalignant lesions (OPL) as well as in established malignant dis-ease and compare it with the healthy controls. Further to evaluate the oxidative stress and antioxidant status in these OPL patients in comparison with the healthy individuals. Methylglyoxal (MG) was determined in thirty two cases of oral precancerous le-sions and thirty two cases malignant cancer patients and compared their findings with thirty-three age/sex-matched controls. Antioxidants and MDA were analyzed to observe the oxidative stress in OPL patients and healthy subjects. The OPL patients were further grouped in two cate-gories based on the extent of oxidative stress and antioxidant status in those patients in order to delineate whether oxidative stress is the sole cause of elevated MG concentration or is there any other factor responsible for elevation in them. The premalignant and malignant cases were con-firmed by histopathological examinations. The MG levels were further compared with the pa-tients with established biochemical cancer markers. Methylglyoxal was determined by method of Racker. Superoxide dismutase, Catalase and Glutathione peroxidase was determined by stan-dard methods. The values were expressed as means ± standard deviation (SD) and data from pa-tients and control was compared using student’s‘t’-test. Serum methylglyoxal levels was found to be significantly elevated (p<0.001) in oral premalignant lesions (OPL) and significantly de-creased levels (p<0.001) in established malignant disease patients compared to healthy controls. Further analysis among oral precancerous lesion patients was based on the oxidative stress and antioxidant status which were categorized into two groups. Serum malondialdehyde levels were significantly higher and antioxidants were significantly lower in (14/32) 43.75% (Group II) OPL patients where as no significant changes were observed in the remaining patients (18/32) 56.25% (Group I) when compared to controls. Levels of methylglyoxal and specific cancer markers in es-tablished cases of malignant disease are shown in Table 1II. Measurement of serum MG levels in suspected OPL- patients will help us to screen the subjects with or without risk of malignant transformation as decreased MG levels increases the risk of malignant change. These high risk subjects could be referred to specialized centers for further evaluation. This could be used as a screening marker which is simple and cost effective.