BACKGROUND Oral submucosal fibrosis (OSMF) is a chronic debilitating fibrotic disease of the oral cavity and is a serious health hazard in south Asia and, increasingly, the rest of the world. The molecular basis behind various treatment modalities to treat OSMF still remains unclear. In this study, we have investigated the in vitro ability of the buccal mucosal cells to reduce the proliferation of the fibroblasts of the fibrotic area in co-culture of cells and also at the molecular levels to reduce the level of connective tissue growth factor (CTGF) in the OSMF fibroblasts (SMF-F). METHODS The study compares isolation, morphological and proliferation kinetics of SMF-F and BMF cells with and without co-culturing with BMEs. In addition, we have compared the mRNA expression levels of CTGF in SMF-F co-cultured BME and non-co-cultured SMF-F cells using validated real-time quantitative PCR (RT-qPCR) method. RESULTS The basic morphological characteristics of SMF-F were similar to BMF, but the former cells had higher proliferation rate in early passages compared to late passage state. We also observed that the CTGF expression levels in SMF-F under co-culture conditions of BME were consistently and significantly downregulated in all four different SMF-F-derived cells from four different patients. CONCLUSIONS Rapid proliferation and collagen synthesis in SMF-F as against BMF cells are the factors that confirm the innate nature of fibrosis fibroblasts (SMF-F). Further, the CTGF expression level in SMF-F was significantly suppressed by BME in co-culture conditions against controls (BMF). Considered together, this suggests that the cell therapeutic candidate of BME could be used in treating OSMF.