Oral cancer is one of the most common neoplasms worldwide with a high mortality rate in spite of advanced treatment modalities which is attributed mainly to delayed diagnosis. It involves a multistage process of changes i.e. from normal to dysplasia, as seen in oral potentially malignant disorders (OPMDs) to eventually, malignancy. Hence, early diagnosis, at the potentially malignant level, can prove beneficial. Methylene Blue (MB) 1%dye, which is otherwise efficacious in detection of cancers of the bladder, stomach etceteraetera, is one such recent diagnostic tool. It is fairly sensitive, simple to use, and with favorable properties similar to Toluidine Blue (TB), otherwise routinely used for oral cancer/OPMD screening. Methylene blue is cheaper and less toxic than TB, which is said to be toxic to fibroblasts and has a probability of inducing mutagenesis, especially if the vitally stained cells are exposed to high energy irradiation like light. However, the use of MB in oral cancer/OPMD screening has not been documented as largely as TB, in the literature. Aim: To evaluate the efficacy and diagnostic reliability of 1 % MB in-vivo staining in the early detection of OPMDs. Methods: A total of 50 cases of both sexes (no specific age range) with clinically diagnosed OPMDs, who visited the outpatient department of Oral Medicine and Radiology, Saraswati Dental College and Hospital, Lucknow (India), were included in the study. Vital staining of the lesions with 1% MB dye was followed by biopsy from the site with maximum dye retention (or based on the clinician’s judgement in clinically suspicious cases with no dye retention); the tissue specimens thus obtained were subjected to histopathological examination (gold standard) for deriving the final diagnosis. The results of histopathological examination and chair-side vital staining were compared subsequently. The inter-reliability Kappa statistic test was used to assess the association of MB uptake and histopathologic diagnosis among the OPMDs. Results: The results revealed a sensitivity of 71.4%, specificity of 62.5%, positive predictive value of 90.9%, and negative predictive value of 29.4%. The overall diagnostic accuracy of this technique was found to be 70% and the p-value showed equivocal significance (p = 0.063). Conclusion: We conclude that the MB dye is an efficacious diagnostic adjunct and a suitable alternative for the routinely used TB dye, for large-scale, community-based OPMD and oral cancer screening programs among high-risk individuals.