Objective: To investigate the correlation between the distribution of Apo lipoprotein E (ApoE) gene polymorphism and the severity of chronic heart failure (CHF) secondary to non-ischemic cardiomyopathy (NICM). Methods: One hundred and twenty patients with CHF due to NICM and one hundred and eighty patients with CHF due to ischemic cardiomyopathy (ICM) treated in our hospital from January 2013 to December 2016 were selected as NICM group and ICM group, respectively. The genomic DNA of the two groups was extracted for the genotyping of epsilon locus of ApoE gene by PCR-RFLP. The left ventricular end-diastolic diameter (LVEDD) and left ventricular ejection fraction (LVEF) were measured by color Doppler ultrasonography. Results: In NICM group, the epsilon 4/4 and epsilon 3/4 genotypes and the frequency of allele epsilon 4 were significantly higher than those in ICM group (P < 0.05); epsilon 2/3 and epsilon 2/4 genotypes and frequency of allele epsilon 2 were significantly lower than ICM group (P < 0.05); but there was no significant difference between both group in epsilon 2/2 and epsilon 3/3 genotypes and e3 frequency (P > 0.05). Logistic regression analysis showed that epsilon 4/4 genotype and allele epsilon 4 were the influencing factors of CHF secondary to NICM (P < 0.05). Patients in the NICM group showed different genotypes and different features in both LVEF and LVEDD, the order of which is: LVEDD (epsilon 4/4) > LVEDD (epsilon 3/4) > LVEDD (epsilon 3/3) > LVEDD (epsilon 2/4) > LVEDD (epsilon 2/3) > LVEDD (epsilon 2/2) (P < 0.05); LVEF (epsilon 4/4) < LVEF (epsilon 3/4) < LVEF (epsilon 3/3) < LVEF (epsilon 2/4) < LVEF (epsilon 2/3) < LVEF (epsilon 2/2) (all P < 0.05). Conclusion: ApoE gene polymorphism is closely related to CHF secondary to NICM, and CHF is more severe in NICM patients with epsilon 4/4 type ApoE gene.