Ezrin, the linker between membrane protein and cytoskeleton, plays an important role in the cellular morphology, cytoskeleton reorganization, adhesion, invasion and metastasis. In this study, ezrin was found to express in high levels either in nasopharyngeal carcinoma tissues or in nasopharyngeal carcinoma 5–8F cells and the knockdown of ezrin expression in the 5–8F cells by RNA interferance could reduce invasive ability, suggesting that ezrin is involved in the progression and invasion of nasopharyngeal carcinoma. Nasopharyngeal carcinoma-associated gene 6 is a novel candidate suppressor gene of tumor metastasis, which was originally cloned in nasopharyngeal carcinoma high-frequency heterozygosity loss region 9p21-22 and is down-regulated in nasopharyngeal carcinoma. In the present study, we hypothesize that nasopharyngeal carcinoma-associated gene 6 plays an inhibitory role in the migration and invasion of nasopharyngeal carcinoma cells via modulating the function of ezrin. Firstly, different mutants of NGX6 were constructed and transfected into nasopharyngeal carcinoma 5–8F cells. The invasion and migration of 5–8F cells overexpressing nasopharyngeal carcinoma-associated gene 6 or mutants were measured. The results showed that enhanced expression of nasopharyngeal carcinoma-associated gene 6 could reduce invasive and migratory abilities of 5–8F cells, and the cytoplasmic domain was essential for nasopharyngeal carcinoma-associated gene 6 to modulate cell migration and invasion. Further experiment results showed that nasopharyngeal carcinoma-associated gene 6 protein was associated with ezrin by its cytoplasm region, and it could down-regulate the expression level of ezrin. These results demonstrated that nasopharyngeal carcinoma-associated gene 6 was probably involved in the modulation of invasive and adhesive ability of nasopharyngeal carcinoma cells by down-regulating the expression level of ezrin.