Certain host genetic polymorphisms in interferon (IFN) signaling pathway genes are reported to be associated with response to IFNalpha therapy. We studied 10 single nucleotide polymorphisms (SNPs) in IFN signaling pathway genes to examine their associations with response to IFN treatment in chronic hepatitis B (CHB) patients. Two hundred and forty-six IFNalpha treatment-naïve CHB patients were enrolled for the present study; all received treatment with IFNalpha alone for 6 months, and the efficacy of the therapy was examined. Ten SNPs in 8 IFN signaling pathway genes were genotyped using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) protocol. There were no significant differences in allele frequencies and genotype distributions of the 10 SNPs between the response and non-response groups that underwent IFNalpha therapy. However, the frequency of a G-T-G-A 2',5'-oligoadenylate synthetase (OAS) haplotype was significantly higher in the non-response group than that in the response group (16.1% vs. 8.7%, p=0.015). Our study suggested that patients with a G-T-G-A OAS haplotype were less responsive to IFNalpha treatment.