Background and Objectives:In India, oral submucous fibrosis (OSF) is a commonly encountered precancerous disorder. It is a disease with a protracted course and characteristic clinical features caused by the habit of consuming areca nut. Histologically, the main pathology is extensive fibrosis of the mucosa. OSF can be categorized into four grades based on histology. Inflammatory cells and keratocytes are stimulated by the areca nut alkaloids, and they release transforming growth factor-beta (TGF-β). It has been advocated to play a major role in OSF pathogenesis by increasing collagen synthesis and preventing collagen degradation. Mast cells (MCs) are the additional key players in the pathogenesis of OSF. There is confusion regarding the functional relationship of MC with TGF-β. Few studies have shown TGF-β can repress MC function, whereas other studies have established that TGF-β is a chemotaxin for MCs. However, there is dearth in literature regarding their interaction in OSF. Hence, this study attempted to show a relationship between TGF-β and MC in different grades of the disease, so as to further explicate the pathogenesis of OSF. Materials and Methods: A total of 48 OSF cases were stained using TGF-β antibody. Its staining intensity and staining area were calculated. Sections from same blocks were also stain MCs using 1% toluidine blue. The number of MCs was counted for all the cases. Expression of TGF-β was correlated with MC count in all OSF grades. Results: On correlating TGF-β and MC between the histologic grades, there was a strong negative correlation for Grade I, moderately positive for Grade II and no correlation for Grade III OSF. Interpretation and Conclusions: Among the different grades of OSF, the correlation between MC and TGF-β varies, depending on the severity of inflammation, and the concentration of TGF-β and further investigation in this field may elucidate their role in determining the severity of OSF.