Abstract Background: Cancer is the one of the common cause of mortality in developed and developing countries. Tobacco in any form is found to induce cancer formation. Oral cancer is a multistage process with progressive changes occurring in genetic and cellular morphology as the disease progresses from the normal to premalignant state and then to malignant state. Recent studies have emphasised that nitric oxide is a highly reactive molecule that interacts with DNA resulting in DNA damage.The objective of the present study was to evaluate the nitric oxide levels in the saliva and buccal epithelial cell DNA damage in patients with oral cancer. Material and methods: In this study nitric oxide levels in saliva and buccal epithelial cell DNA damage were estimated in 20 healthy individuals without oral lesions and 20 patients with oral cancer. Results: The mean values of salivary nitric oxide levels were significantly greater in oral cancer patients (126.2155+/- 2.7587) when compared to that of controls (76.111+/-μM/L). Similarly the extent of DNA damage was higher in subjects with oral cancer (28.099+/- 1.2696) than in controls (9.15+/- 0.9131). Pearson's correlation between nitric oxide levels in saliva and extent of DNA damage were found to be moderately correlated in controlsr=0.491 (p<0.01) and in oral cancer patientsr=0.428 (p<0.01). Conclusion: The results of present study illustrate an active involvement of nitric oxide which is derived from tobacco and its related products in the initiation of DNA damage and subsequent formation of oral cancer.