Abstract: Objective To find genes associated with malignant activities of human nasopharyngeal carcinoma cell CNE-2L2. Methods Differential display of proteins between the CNE-2L2 cell with high malignant activities (called W cell) and the CNE-2L2 cell with profound reduced malignant activities (called AS cell) was analyzed by proteomic technique. The differential display was validated by real-time PCR or immune fluorescence staining. Expression of CD44 gene was inhibited by means of siRNA. The inhibition was validated by means of Western blotting. Tumorigenesis of cells was examined in nude mice. Results MOLDI-TOF MS showed 12 protein spots differential displayed. They were: Peroxiredoxin 2 isoform b；Tropomyosin 3；TPM4-ALK fusion oncoprotein type 2；MLL protein；CD44；Retinoblastoma binding protein 7；Tubulin, b polypeptide；ATP synthase，H+ transporting, mitochondrial F1 complex, b polypeptide；Vimentin；D21S2056E protein；Proteasome (prosome, macropain) 26S subunit, non-ATPase，4；ENO1 protein。The former 4 were up-regulated and the latter 8 down-regulated in AS cell. The differential display of the 7 proteins with highest scores was confirmed. Tumorigenesis of the CNE-2L2 cell with inhibition of CD44 gene expression caused by siRNA in nude mice was profoundly inhibited. Conclusion Proteomic analysis showed 12 proteins differential displayed between AS cell and W cell. Inhibition of CD44 gene expression resulted in profound reduction of the malignant activities of CNE-2L2 cell.