The first step in the infection of human T lymphocytes by human immunodeficiency virus type 1 (HIV-1) is attachment to the target cell receptor, the CD4 antigen. This step may be vulnerable to attack by antibodies, chemicals, or small peptides. One of the goals of our therapy research effort is to define drugs which attack HIV at multiple steps of its life cycle, including the initial binding step. Dextran sulfate (molecular weight approximately 8,000), which has been given to patients as an anticoagulant or antilipemic agent for more than two decades, was found to block the binding of virions to various target T lymphocytes, to inhibit syncytia formation, and to exert a potent inhibitory effect against HIV-1 in vitro at concentrations that could conceivably be attainable in human beings. This drug also suppressed the replication of HIV-2 in vitro. These observations could have theoretical and clinical implications in the strategy to develop drugs against HIV types 1 and 2.