Abstract: A hologram quantitative structure-activity relationship (HQSAR) studies were conducted on a series of 54 benzimidazole 5-carboxylic amide derivatives as HCV NS5B polymerase inhibitors.The influences of molecular fragment parameter,fragment distinction parameter and molecular holographic length on the HQSAR models were investigated.The optimal HQSAR model was obtained for the 39 training set compounds showing cross-validated q2 value of 0.779,conventional r2 value of 0.922 and stand deviation SEE value of 0.251.The color code analysis based on the obtained HQSAR model provided useful insights into the chemical and structural features of these inhibitors for their NS5B polymerase inhibitory potency.Based on the best model HQSAR,17 new 2-sulfur acetyl aromatic aminebenzimidazole-5-carboxylic acid amide derivatives were designed and screened using the optimal HQSAR model,giving potential candidates with high predictive HCV NS5B polymerases inhibitory activity.