Abstract The three dimensional-quantitative structure activity relationship (3D-QSAR) study was performed on a series of 4-hydroxyamino α-pyranone carboxamide analogues using comparative molecular similarity indices analysis (COMSIA). The purpose of the present study was to develop a satisfactory model providing a reliable prediction based on 4-hydroxyamino α-pyranone carboxamide analogues as anti-HCV (hepatitis C virus) inhibitors. The statistical results and the results of validation of this optimum COMSIA model were satisfactory. Furthermore, analysis of the contour maps helped to provide guidelines for finding structural requirement. Therefore, the satisfactory results from this study may provide useful guidelines for drug development of anti-HCV inhibitors.