Substituted Schiff bases of 1-amino-3-hydroxyguanidine (SB-HAG) were tested for the first time against noninfected T4 lymphocytes (CEM-6 cells) and the same cell line infected by HIV-1 in vitro. Twenty-one of 23 compounds at micromolar levels did not inhibit the growth of the noninfected T4 cells, suggesting minimal cytotoxicity. The antiviral effects of these compounds in a micromolar concentration range have been shown to be nonsignificant (less than 30%) against HIV-1. Three-dimensional parameter focusing of the physicochemical properties (i.e., log P and VW) and the marginal antiviral activities shows that the marginally active compounds lie in a region different from the inactive compounds. QSAR analysis of the two subsets shows that the cytotoxicity correlates well with the electronic and lipophilic parameters. The results of the QSAR analysis can serve as guidelines for further structural modification of this series of compounds to minimize the cytotoxicity against host cells.