Jacalin is a plant lectin known to specifically induce the proliferation of CD4+ T lymphocytes in human. We demonstrate here that jacalin completely blocks human immunodeficiency virus type 1 (HIV-1) in vitro infection of lymphoid cells. Jacalin does not bind the viral envelope glycoprotein gp120. Besides other T cell surface molecules, it interacts with CD4, the high-affinity receptor to HIV. Binding of jacalin to CD4 does not prevent gp120-CD4 interaction and does not inhibit virus binding and syncytia formation. The anti-HIV effect of the native lectin can be reproduced by its separated alpha-subunits. More importantly, we have defined in the alpha-chain of jacalin a 14-amino acid sequence which shows high similarities with a peptide of the second conserved domain of gp120. A synthetic peptide corresponding to this similar stretch also exerts a potent anti-HIV effect. This peptide is not mitogenic for peripheral blood mononuclear cells and does not inhibit anti-CD3-induced lymphocyte proliferation. These results make jacalin alpha chain-derived peptide a potentially valuable therapeutic agent for acquired immunodeficiency syndrome.