Context: Recently, non-communicable diseases have snatched the lead from infectious diseases in causing mortality. Of these, oral cancer accounts for a significant proportion of deaths. Every year in India significant percentage of newly diagnosed malignancy is oral cancer attributed to various reasons. Aims: The aim of this study was to assess the extent of oxidative stress and its effect on modification of DNA by urinary nucleoside 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in oral cancer subjects. To see the relationship between the nucleoside 8-OHdG and antioxidant capacity ferric reducing ability plasma (FRAP) in oral cancer subjects. Settings and Design: Case–control study included three groups with 60 volunteers, who were divided into 30 controls, and equal number of clinically diagnosed oral cancer male patients: (Subdivided into newly diagnosed [n = 15] and 1-year treatment follow-up oral cancer subjects [n = 15]). Materials and Methods: A random urine sample was used for analysis of 8-OHdG concentration. Serum triglycerides, lipid peroxidation, protein thiols, and FRAP assay were performed by spectrophotometric technique. Statistical Analysis Used: Student's t-test and one-way analysis of variance were performed for group comparison and Pearson's correlation analysis were used. A P < 0.05 was considered the optimum level of significance. Results: The urinary 8-OHdG and serum malondialdehyde levels were significantly elevated in newly diagnosed oral cancer subjects in their 1-year treatment compared to the control group (P < 0.05). A significant correlation was observed between urinary 8-OHdG and FRAP in both groups of oral cancer subjects. Conclusions: Urinary 8-OHdG can be a useful diagnostic marker of oxidative DNA damage in oral cancer subjects.