miR-21 as a tumor oncogenic molecule has been reported. However, whether miR-21 can affect the sensitivity of oral squamous cell carcinoma (OSCC) cells to cisplatin remain unclear. The aim of this study is to evaluate the roles of miR-21 in the sensitivity of OSCC cells to cisplatin. RT-PCR assay was performed to detect the expression of miR-21 in 10 pairs of OSCC and noncancerous tissue samples. Then As-miR-21 oligonucleotides were used to down the miR-21 expression. Finally, the effects of miR-21 downregulation the sensitivity of OSCC cells (CA-27) to cisplatin in vitro were also detected. The level of miR-21 expression in OSCC tissues was significantly higher than that in corresponding noncancerous tissues. Down the expression of miR-21 could significantly inhibit growth and induce apoptosis of CA-27 cells. Moreover, downregulation of miR-21 could sensitize CA-27 cells to cisplatin possibly by increasing cisplatin induced apoptosis. This study demonstrated that combination of cisplatin application with miR-21 downregulation might be a potential strategy for the treatment of human OSCC.