Hepatitis B virus (HBV) causes chronic infection in 250 million people worldwide. Chronic HBV carriers have a high risk of fibrosis, cirrhosis, and hepatocellular carcinoma. Drug resistance often develops during long-term antiviral treatment using HBV polymerase/reverse transcriptase inhibitors, making anti-HBV therapies as well as drug development more complicated. In this paper, a machine learning method based on large scale of gene expression profiles was used for anti-HBV drug screening.