CD147 (basigin, EMMPRIN) is a widely distributed cell surface glycoprotein that belongs to the Ig superfamily. It is highly expressed on the surface of malignant tumor cells to promote their invasiveness and chemo-resistance. The present study aimed to reveal the anti-apoptotic effect of CD147 on the multi-drug resistant (MDR) phenotype of human oral squamous carcinoma cells (SCC) and its possible pathways. Data presented herein showed that MDR derivative SCC KB/V cell line expressed significantly higher CD147 and X-linked inhibitor of apoptosis (XIAP) than its sensitive counterpart KB cells by RT-PCR and Western blot analysis. Down-regulation of CD147 by transfection with CD147 siRNA resulted in decreased XIAP expression. Flow cytometric analysis and electron microscopic observation revealed differential cell apoptotic status related to CD147 expression. Additionally, chemo-sensitivity to 5-fluorouracil of KB/V was increased by CD147 silencing as measured by MTT colorimetric assay. These results suggest that inhibition of CD147 and subsequent XIAP depletion may have an anti-tumor effect through enhancing the susceptibility of cancer cells to apoptosis.