HIV-infected cells producing virions express the viral envelope glycoprotein gp120/gp41 on their surface. We examined whether liposomes coupled to recombinant soluble CD4 (sCD4, the ectodomain of CD4 which binds gp120 with high affinity) could specifically bind to HIV-infected cells. sCD4 was chemically coupled by 2 different methods to liposomes containing rhodamine-phosphatidylethanolamine in their membrane as a fluorescent marker. In one method, sCD4 was thiolated with N-succinimidyl acetylthioacetate (SATA) and coupled to liposomes via a maleimide-derivatised phospholipid. In the other method, the oligosaccharides on sCD4 were coupled to a sulfhydryl-derivatised phospholipid, utilizing the bifunctional reagent, 4-(4-N-maleimidophenyl)butyric acid hydrazide (MPBH). The association of the liposomes with HIV-1-infected or uninfected cells was examined by flow cytometry. CD4-coupled liposomes associated specifically to chronically infected H9/HTLV-IIIB cells, but not to uninfected H9 cells. CD4-coupled liposomes also associated specifically with monocytic THP-1 cells chronically infected with HIV-1 (THP-1/HIV-1IIIB). Control liposomes without coupled CD4 did not associate significantly with any of the cells, while free sCD4 could competitively inhibit the association of the CD4-coupled liposomes with the infected cells. The chimeric molecule CD4-immunoadhesin (CD4-IgG) could also be used as a ligand to target liposomes with covalently coupled Protein A (which binds the Fc region of the CD4-IgG) to H9/HTLV-IIIB cells. The CD4-liposomes inhibited the infectivity of HIV-1 in A3.01 cells, and also bound rgp120. Our results suggest that liposomes containing antiviral or cytotoxic agents may be targeted specifically to HIV-infected cells.