Aim: The role of blood cholesterol level variations in diagnosis and treatment has been extensively worked on in many studies. However, studies on alteration in serum lipid profile among OSMF patients are limited. The present study was performed to estimate serum lipid profile in OSMF patients and gutkha chewers. Material and Methods: The study sample comprised of 45 cases, which included 15 clinically diagnosed OSMF patients (group I), 15 persons with gutkha chewing habit (group II) and 15 controls. The serum levels of Total serum cholesterol (TC), Low Density Lipoproteins (LDL), High Density Lipoproteins (HDL), Very Low Density Lipoproteins (VLDL) and Triglycerides (TG) were analyzed. The data was analyzed using Post hoc Dunnett’s t-test and P<0.05 was studied as statistically significant. Results: On analysis serum lipid profiles progressively lowered in Gutkha chewers and OSMF patients. There was significant decrease in TC (P<0.0001), TG (P<0.0002), LDL (P<0.0007) and VLDL (P<0.0004), HDL (P=16) in gutkha chewers and OSMF patients as compared to controls. Conclusion: This reduction in serum lipid levels can be used as a support for diagnosis and prognosis of oral premalignant and malignant lesions. Further studies with larger sample size and long term follow up and estimation of lipid profiles with regular intervals is required to prove correlation between conversions from precancerous condition to malignancy.