Interferon-alpha therapy has become a main stay of treatment for hepatitis-B patients. The sustained remission rates are around 30%, and the factors determining response are poorly defined. Our study aimed to search for the genetic differences between responder and non-responder patients. We have found 13 short tandem repeat markers (STR) that display different allele and/or genotype frequency between the two patient groups. Eleven out of 13 STR markers were selected to perform principal component analysis and hierarchical clustering. The study subjects could be further divided into six groups based on their genetic similarity, which correlated with the drug response rate. In conclusion, this pilot study has developed a new approach to identify genetic markers that allows us to predict the drug response in hepatitis B patients. Our study utilizing STR markers may provide an alternative approach to the utilized SNP markers in pharmacogenetic study.