Abstract Introduction : The immune microenvironment is essential in the development of leukoplakia. Which is a potentially precancerous lesion with increased chances of evolving into oral squamous cell carcinoma (OSCC). The immune check point proteins V-domain Ig Suppressor of T-cell Activation (VISTA) and cytotoxic T lymphocyte antigen-4(CTLA-4) are the most important co stimulatory molecule the playa a key role in negative regulation of T cell during process of carcinogenesis. The VISTA and CTLA-4 serves as a emerging new biomarker in early detection and to determine malignant potential of leucoplakia Material and method: Tissue samples from patients with suspected oral malignant lesions were analyzed using immunohistochemistry (IHC). The expression levels of CTLA-4 and VISTA were evaluated using standardized scoring systems. Clinical finding and histopathological grading was established . The correlation between protein expression patterns and clinicopathological parameters was statistically analyzed. Result : VISTA expression varied among the different dysplasia grade with a non-linear relationship observed between VISTA expression and the severity of dysplasia.A distinct progressive rise in CTLA 4 positivity that paralleled the severity of dysplasia, indicating that CTLA 4 expression could serve as a valuable biomarker for evaluating the risk of malignant transformation in oral potentially malignant disorders Keywords: CTLA-4, VISTA, leukoplakia, immune checkpoint proteins, immunohistochemistry, inflammatory check points