HIV infection is initiated when the virus envelope glycoprotein (Env) binds to CD4 and CCR5 molecules on the surface of host T cells. However, attempts to use CD4-Ig constructs to prevent virus-cell binding have so far proved unsuccessful. Now, Gardner et al. describe the development of eCD4-Ig, a fusion of CD4-Ig with a sulfopeptide mimetic of the amino terminus of CCR5. eCD4-Ig bound avidly and cooperatively to Env, efficiently neutralizing 100% of a diverse panel of previously neutralization-resistant HIV1, HIV2 and simian immunodeficiency virus (SIV) isolates. Rhesus macaques inoculated with an adeno-associated virus–eCD4-Ig construct stably expressed eCD4-Ig for more than 40 weeks and were protected from several SIV challenges.