The new D-mannose-specific lectin fromGerardia savagliais shown to prevent infection of H9 cells with human immunodeficiency virus type 1 (HIV-1; strain HTLV-IIIB). At a concentration of 0.2 μM, complete protection was achieved. Even at a 50-fold higher concentration, this lectin is not toxic for the cells. Moreover, the lectin inhibits syncytium formation in the HTLV-IIIB/H9-Jurkat cell system to 100% at 0.2 μ.M. This effect was abolished by coaddition of D-mannose at a stoichiometric ratio of lectin to sugar of 1:500. The lectin-caused inhibition of syncytia formation was observed also in the HIV-1/human lymphocyte system. Perhaps more importantly, it is shown that the lectin reacts with the oligosaccharide side chains of the HIV-1 gpl20 env molecule, which very likely can be classified to the high-mannose oligosac-charides. These data provide the basis for a rational screening for compounds interfering with gpl20-CD4 interactions.