Interferon alfa (IEN-α) therapy remains a mainstay of treatment in active hepatitis B. However, sustained remission rates remain relatively low, and the search for factors important for response to therapy continues. Our study aimed to identify the host single nucleotide polymorphisms (SNPs) that predict IFN response in hepatitis B patients. We selected genes in the IFN pathway involved in antiviral and signaling activities and sequenced 22 SNPs for each of our 82 patients. Our results identified 2 SNPs in the antiviral pathway that may influence IFN response. One SNP in the regulatory region of the eIF-2α gene revealed A/G alleles. The rate of A/G heterozygotes is 22% in nonresponders (NR) and 2% in sustained responders (R), with an odds ratio (OR) of 12.82 (95% CI: 1.52–107.85, P = 0.009). After adjustment for age, sex, and HBV DNA level, the OR reaches 14.94 (95% CI: 1.45–153.71, P = 0.023). This marker revealed greater significance than HBV DNA levels (OR 5, 95% CI: 1.01–2.43, P = 0.033) as a marker for IFN response, suggesting its potential advantage over conventional predictors. In addition, borderline significance for the SNP in MxA gene promoter at nt –88 revealed G/T alleles, with the G/T heterozygote rate being 19% in nonresponders and 43% in sustained R (P = 0.061), concurring with a previous study involving hepatitis C patients. In conclusion, this pilot identified SNPs as potential markers that could predict hepatitis B patient response. These observations may help guide future large-scale studies in examining host SNPs for their clinical utility in predicting IFN response. (HEPATOLOGY2002;36:1416–1424).