Aim To investigate the effects of Ezrin gene knockout on calpain-1 activity and adenosine triphosphate binding cassette transporter A1(ABCA1) protein levels in RAW264.7 cells. Methods RAW264.7 cells transfected with small interfering RNA (siRNA) targeting Ezrin were subject to real time PCR and Western blot to detect the inhibition ratio. Added with angiotension Ⅱ(AngⅡ) or AngⅡ+ Ezrin siRNA, calpain-1 protein expression and activity were determined by using Western blot. Then, the expression of ABCA1 protein was examined by Western blot after the treatment with AngⅡ,Ezrin siRNA, calpain inhibitor N-acetyl-L-leucyl-L-leucyl-L-norleucine (ALLN). Results Ezrin mRNA and protein expression in Ezrin siRNA groups were inhibited(P<0.05). The calpain-1 expression were upregulated by AngⅡ treatment (4.92±0.23 vs 1.00±0.17, P<0.05), which were reversed by Ezrin siRNA (0.23±0.21 vs 4.92±0.23, P<0.05). Therefore, the ABCA1 protein expression was inhibited by addition of AngⅡ(0.167±0.055 vs 0.732±0.072), which were reversed by Ezrin siRNA (0.611±0.048 vs 0.167±0.055, P<0.05). There were no statistically significant differences at ABCA1 protein levels between AngⅡ+Ezrin siRNA group and AngⅡ+Ezrin siRNA+ALLN group. Conclusion Ezrin might play an important role in AngⅡ-induced ABCA1 protein attenuation via calpain-1 pathway.