Purpose of Review <p>CD133, a cancer stem cell marker, has been implicated in the malignant progression of various cancers, including oral squamous cell carcinoma (OSCC). However, its utility in predicting the risk of malignant transformation in oral potentially malignant disorders (OPMDs) remains unclear. This systematic review aimed to evaluate the expression of CD133 in OPMDs and determine its association with the risk of malignant transformation.</p> Recent Findings <p>A comprehensive search was conducted across PubMed, Scopus, Web of Science, Cochrane Library, and Google Scholar from inception to September 2025. Studies assessing CD133 expression in OPMDs and its link to malignant transformation were included. Summary data on CD133 expression and a fixed-effect meta-analysis of the risk ratio (RR) were performed. Heterogeneity, publication bias, and study quality were also evaluated. Of 267 articles screened, 8 studies comprising 711 cases (438 OPMDs and 197 OSCC) met the inclusion criteria. CD133 expression was consistently higher in OSCC compared to OPMDs. Meta-analysis revealed that OPMDs with positive CD133 expression had a significantly elevated risk of malignant transformation compared to those without expression (OR 8.55 [4.00; 18.30]).</p> Summary <p>This review demonstrates a significant association between CD133 expression and the risk of malignant transformation in OPMDs, particularly in leukoplakia and oral lichen planus. CD133 may serve as a potential predictive biomarker for identifying high-risk OPMDs and guiding early intervention strategies.</p>