The structure-activity relationships of nucleoside analogs with antiviral activity were studied utilizing structure-activity maps (SAMs). SAMs are chemical structures, quantified by molecular descriptors, plotted against their biological activities. The molecular descriptor number of atoms and bonds of a molecule (NAB) was used to quantify the chemical structures. The cytotoxicity measurement used in this study was the 50% cytotoxic dose (CD50) in (M, and the antiviral activity measurement used in this study was the 50% effective dose (ED50) in (M. The SAMs were examined for compounds grouped according to NAB. The topoisomer groups (based on NAB) were examined to determine important activity trends utilizing structural orderings and structural transformations. SAMs were used to systematically identify the effects of chemical modification on the antiviral activity of nucleoside analogs and to determine the site and type of modifications for improved activity and reduced toxicity of potential antiviral agents.