Background: Oral cancer patients are found to have poor clinical outcome and high disease recurrence rate, in spite of an aggressive treatment regimen. The inactivation of INK4A/ARF loci is reported to be second to p53 inactivation in human cancers. The purpose of this study was to assess the prognostic significance of the molecular aberrations in the INK4A locus for effective identification of aggressive oral carcinoma cases needing alternate therapy. Materials and Methods: The study composed of 116 patients freshly diagnosed with oral carcinoma. The genetic and epigenetic status of the p16 INK4A and p14ARF genes was evaluated. The relation between these genic alterations and different treatment end points, such as residual disease (initial response), disease recurrence, and overall survival, along with the standard clinical markers, were analyzed. Results: 62% of the study cases had p16INK4A gene abnormalities, with deletion accounting for 33% and methylation for 29%. Alterations in p14 ARF gene either by deletion (12%) and/or methylation (18%) were