Four sulfonic acid polymers [poly(4-styrenesulfonic acid)(PSS), poly(anetholesulfonic acid)(PAS), poly(vinylsulfonic acid)(PVS), poly(2-acrylamido-2-methyl-1-propanesulfonic acid)(PAMPS)] have been found to inhibit the cytopathicity of HIV-1 and HIV-2 in MT-4 cells at concentrations that are not toxic to the host cells. The sulfonic acid polymers also inhibited syncytium formation in co-cultures of MOLT-4 cells with HIV-1- or HIV-2-infected HUT-78 cells. They also inhibited binding of anti-gp120 mAb to HIV-1 gp120 and blocked adsorption of HIV-1 virions to MT-4 cells. PSS and PAS, but not PVS and PAMPS, interfered with the binding of OKT4A/Leu3a to the CD4 receptor. The anti-HIV activity of these polyanionic compounds can be ascribed to inhibition of the gp120-CD4 interaction. Sulfonic acid polymers represent a lead of anti-HIV compounds that warrant further evaluation of their therapeutic potential.