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Aims: To estimate the serum fucose levels in clinically and histopathologically diagnosed oral cancer, oral leukoplakia, and oral submucous fibrosis cases. To compare and correlate the severity of dysplasia or histopathological grading of the premalignant and malignant lesions with serum fucose levels. Objective: To determine the role of serum fucose as a reliable biomarker for early detection of malignant transformation of potentially malignant lesions and conditions and prediction of biologic behavior of the malignant lesions. Material and Method: The intended study shall include 100 participants divided into 4 groups. Groups I, II, and III will include 25 clinically and histological diagnosed cases of oral leukoplakia, oral submucous fibrosis, and oral cancer, and 25 normal control group. Fucose was measured according to the method of Dische and Shettles as adopted by Winzler. Statistical Analysis: Statistical analysis will be done using SPSS statistical software (Version 10), and the levels of significance will be analyzed using the paired and unpaired t -tests. Result: In subjects of 4 groups were age- and gender-matched and comparable thus these may also not influence the study outcome measure (fucose levels). ANOVA revealed significantly different fucose levels among the groups ( F = 17.00, P < 0.001). Mean fucose level did not differ ( P > 0.05) between oral leukoplakia, oral submucous fibrosis, and oral cancer (84.5%) groups. The increase in mean fucose levels with severity was the highest in the oral cancer group followed by oral submucous fibrosis and oral leukoplakia group. The mean fucose levels did not differ between mild and moderate grades ( P > 0.05) in all the 3 groups. Conclusion: The evaluation of serum l-fucose would be of good help in assessing early malignant change in increasing the accuracy of clinical diagnosis and also in assessing the spread and invasiveness of oral cancer, oral submucous fibrosis, and leukoplakia.