Aim To explore the hyperhomocysteinemia （HHcy） inhibit cystic fibrosis transmembrane conductance regulator （CFTR） expression of apolipoprotein E-knocked-out （ApoE^－/－） mice renal via endoplasmic reticulum stress （ERS）. Methods 18 male ApoE^－/－ mice were randomly divided into 3 groups （n＝6 for each group）: ApoE^－/－control group,high methionine group and intervention group. They were respectively fed with nomal diet and high methionine diet and high methionine diet plus 0.006% folate and 0.0004% vitamin B₁₂ for 14 weeks. After 14 weeks,the blood of the mice was gotten using a unilateral enucleation method,the serum homocysteine （Hcy） was detected by enzyme-linked immunosorbent assay （ELISA）. The protein and mRNA expressions of CFTR in the renal of mice were detected by immunohistochemical assay and real time polymerase chain reaction （RT-PCR） the mRNA expressions of glucose regulated protein 78 （GRP78）,activating transcription factor 6 （ATF6）,protein kinase RNA-like endoplasmic reticulum kinase （PERK）,C/EPB homologous protein （CHOP） in the renal of mice were detected by RT-PCR. Results The result showed that the content of Hcy was significantly higher in ApoE^－/－control group,high methionine group and intervention group an remarkable increase was observed in the high methionine group （P<0.01）. The results of RT-PCR and immunohistochemical assay exposed a remarkable down-expressed CFTR mRNA and protein in high methionine group （P<0.01）. The results of RT-PCR exposed a remarkable up-expressed GRP78,ATF6,PERK,CHOP mRNA in high methionine group,while intervention group decreased GRP78,ATF6,PERK,CHOP levels compared with high methionine group. There were negative correlations between GRP78,ATF6,PERK,CHOP mRNA and CFTR mRNA （r＝－0.7192,P<0.01 r＝－0.5501,P<0.01 r＝－0.7772,P<0.01 r＝－0.6785,P<0.01）. Conclusion HHcy inhibits CFTR expression of ApoE-knockout mice renal might via endoplasmic reticulum stress.