Different chimeric antibody-like molecules consisting of the four human CD4 extracellular domains (amino acids 1–369) fused to different parts of human IgG₁ and IgM heavy-chain constant regions have been created and expressed in mammalian cells. For both IgG₁ and IgM fusion proteins, the best expression in COS cells was observed for molecules lacking the CH1 domain of the heavy-chain constant region. The chimeric molecules are potent inhibitors of human immunodeficiency virus (HIV) infection and HIV–mediated cytotoxicity. A CD4:IgG₁ hinge fusion protein, which was analyzed in more detail, binds efficiently to HIV gpl60 and human Fc receptors and shows complement-assisted inhibition of viral propagation in culture. Half-life studies after intravenous application of the latter human fusion protein into mice and monkeys showed significant prolongation of serum survival compared to soluble CD4. An IgG_2b murine homolog of the human CD4:IgG₁ hinge fusion protein was prepared and evaluated in mice, where it was found to be nontoxic and to have no detectable effect on the humoral response to soluble antigen.