The development of oral cancer proceeds through discrete molecular changes that are acquired from loss of genomic integrity after continued exposure to environmental risk factors. It is preceded in the majority of cases by clinically evident oral potentially malignant disorders, the most common of which is leukoplakia. Early detection of these oral lesions by screening methods using suitable markers is critical as it mirrors molecular alterations, long before cancer phenotypes are manifested. Assessment of salivary interleukin-6 (IL-6) as a marker of malignant progression was undertaken in patients with leukoplakia having coexisting periodontitis (n = 20), periodontitis patients without leukoplakia (n = 20), and healthy controls (n = 20) by competitive enzyme-linked immunosorbent assay. Results showed elevation of IL-6 levels in leukoplakia with coexisting periodontitis and in periodontitis patients when compared to healthy control (P < 0.001). Within the leukoplakia group, IL-6 level was found to be increased with increase in the severity of dysplasia. The use of tobacco was seen to play a significant role in the elevation of salivary IL-6.The importance of IL-6 as a specific marker for leukoplakia with dysplasia and the role of tobacco as an independent risk factor has been highlighted.