Abstract: Objective To investigate the effect of human concentration nucleoside transporters 1(hCNT1/SLC28A1) and multi-drug resistance protein 4(MRP4/ABCC4) gene polymorphism on the response of chronic hepatitis B patients to nucleoside analogues treatment. Methods There were 136 patients of chronic hepatitis B treated with entecavir (68) or telbivudine (68). The allele and gene frequency distributing of the four loci of hCNT1/SLC28A1 and MRP4/ABCC4 as well as the polymorphisms were detected in all patients by multiplex snapshot single base extension method. Based on the treatment response, the patients were divided into primary partial response (PPR) group and complete viral response (CVR) group, hCNT1/SLC28A1 and MRP4/ABCC4 gene polymorphism between these two groups were analyzed. Results The rates of PPR and CVR were 56.6% (77/136) and 43.4% (59/136) respectively. There was no statistical difference in baseline HBV DNA value, hepatitis B virus genotype and HBeAg status between PPR and CVR groups (P=0.148, P=0.622,P=0.071) .The distribution of allelotype rs2290272 C/T and rs11568658 G/G in PPR group were higher than those in CVR CM(155mmgroup (P=0.043, P=0.049). Haplotype of C/A/T/C and C/C/G/G in CVR group were higher than those in PPR group (P=0.024,P=0.005). Conclusion The single nucleotide polymorphisms (SNPs) of two candidate genes, including rs2290272 C/T of hCNT1/SLC28A1 and rs11568658 G/G of MRP4/ABCC4, may weak the response of chronic hepatitis B to nucleoside analogues treatment, as well as haplotype of C/A/T/C and C/C/G/G may enhance the response.