Purified recombinant soluble CD4 (rCD 4) is a new antiviral agent which has been shown to block HIV infection of lymphocytic and monocytic cell lines as well as peripheral blood mononuclear cells. The authors investigated here the ability of rCD4 to inhibit HIV-1 infection of peripheral blood macrophages. In this system, purified preparations of rCD4 provided, at concentrations above 10 micrograms/ml, a complete protection against a challenge with the monocytotropic strain HIV-1 Ba-L. Also, anti-CD 4 monoclonal antibodies directed at the V1 domain of the CD 4 molecule blocked infection of macrophages by HIV. Recombinant CD 4 is therefore a potent antiviral agent able to prevent HIV-1 infection of peripheral blood macrophages, and the CD 4 molecule is likely to be the main HIV receptor on these cells.