AIDS is an immunoregulatory disorder characterized by depletion of the CD4⁺, helper/inducer lymphocyte population¹. The causative agent of this disease is the human immunodeficiency virus, HIV^2–4, which infects CD4⁺ cells and leads to cytopathic effects characterized by syncytia formation and cell death^5,6. Recent studies have demonstrated that binding of HIV to its cellular receptor CD4 is necessary for viral entry^7,8. We find that binding of HIV to CD4 induces rapid and sustained phosphorylation of CD4 which could involve protein kinase C. HIV-induced CD4 phosphorylation can be blocked by antibody against CD4 and monoclonal antibody against the HIV envelope glycoprotein gp120, indicating that a specific interaction between CD4 and gp120 is required for phosphorylation. Electron microscopy shows that a protein kinase C inhibitor does not impair binding of HIV to CD4⁺ cells, but causes an apparent accumulation of virus particles at the cell surface, at the same time inhibiting viral infectivity. These results indicate a possible role for HIV-induced CD4 phosphorylation in viral entry and identify a potential target for antiviral therapy.