Background: Cancer of Oral cavity is an important cancer globally. It remains a major cause of mortality and morbidity throughout the world. In India, because of cultural, geographic factors and the popularity of addictive habits, the frequency of oral cancer is high. Patients with malignant tumors induce various degrees of metabolic derangements. Substantial information has been obtained in the past decades on the role of arginine in tumor growth. Arginine has several important benefits including promotion of protein/collagen synthesis, wound healing and support of the immune system. Disturbances in arginine metabolism possibly contribute to events that lead to cancer cachexia. The net beneficial or negative effect depends on how arginine is metabolized and the strength of the activities of each of these arginine-catabolizing enzymes: Nitric Oxide Synthase and Arginase. Relative changes in these enzymatic activities serve as major determinants of Nitric Oxide (NO__ampersandsignbull;) production. In view of this, the present study was planned to estimate the serum levels of NO__ampersandsignbull; and arginase activity in oral cancer patients and to compare them with age, sex matched healthy controls. Material and Methods: Fifty histopathologically proved cases of oral cancer from any stage (Stage I to stage IV) in the age group of 40-75 years admitted in Sassoon Hospital, Pune and fifty age, sex matched healthy controls were recruited for this study. Intravenous blood sample was obtained to evaluate study parameters. Arginase activity was estimated by Roman and Ray method while NO__ampersandsignbull; levels were measured by Cortas and Wakid method. Results: The results of this study showed significant increase in the activity of arginase when compared with controls and activity was found to be significantly increased in stages III+IV when compared with stages I+II (p __ampersandsignlt; 0.01). Nitric oxide level was found to be significantly increased in oral cancer condition when compared to normal individuals (p__ampersandsignlt;0.01). Comparison of nitric oxide levels between stages I+II and stages III+IV showed further rise (p __ampersandsignlt; 0.05). Conclusion: We can conclude that both nitric oxide and arginase might be playing important role in carcinogenesis and tumor progression in oral cancer patients. The estimation of these two parameters can give additional insight regarding disease progression.