Human blood plasma, serum, peripheral blood mononuclear cells, and erythrocytes contain significant amounts of inorganic polyphosphates (ranging from 53 to 116 microM, in terms of phosphate residues). Here we demonstrate that at higher concentrations linear polyphosphates display cytoprotective and antiviral activity. Sodium tetrapolyphosphate and the longer polymers, with average chain lengths of 15, 34, and 91 phosphate residues, significantly inhibited human immunodeficiency virus type 1 (HIV-1) infection of cells in vitro at concentrations > or = 33.3 microg/ml (> or = 283-324 microM phosphate residues), whereas sodium tripolyphosphate was ineffective. In the tested concentration range, these compounds had no effect on cell growth. The longer-chain polyphosphates (polyphosphates with mean chain lengths of 15 and 34) but not sodium tripolyphosphate and sodium tetrapolyphosphate also inhibited HIV-1-induced syncytium formation at a concentration of 160 microg/ml (1.51-1.54 mM phosphate residues). The results obtained with the syncytium assay and by cell-virus binding experiments indicate that the anti-HIV effect of these nontoxic polyanions may be caused by binding of the compounds to both the host cell surface and the virus, thereby inhibiting adsorption of the virus. Competition experiments revealed that binding of [32P]polyphosphate to Molt-3 cells was only partially inhibited by the antibody OKT4A.