Retroviral vectors have been developed which produce a secreted form of the helper/inducer T-cell antigen, CD4. Amphotropically packaged vectors were used to transduce cells, and these cells were shown to express the secreted CD4 (sCD4) gene product. The sCD4 produced by the viral vectors is immunoprecipitated by monoclonal antibodies against CD4, which specifically block human immunodeficiency virus (HIV) infection of helper/inducer T cells. A direct physical interaction of vector-produced sCD4 and HIV-1 gp120 was demonstrated by coprecipitation of sCD4/gp120 with antiserum directed against HIV gp120. Furthermore, transduced cells producing sCD4 can protect HIV-susceptible cells from infection by HIV. These data suggest that gene therapy is a potential approach for the treatment of AIDS.