AbstractIt has recently been shown that disulfide bond Cys130—Cys159 in domain 2 of monomeric CD4 is involved in the formation of CD4 disulfide‐bonded dimers on cell surfaces and that it can influence the permissiveness of cells to HIV infection. Because this disulfide bond is buried in the monomer, a large conformational change must take place in order to allow for such disulfide exchange. Using standard optimization techniques, whose efficiency was first checked in the well‐documented CD2 case, we have shown that 3D domain swapping is a likely candidate for the conformational change, the hinge loop, or linker, being loop E—F. Indeed, as a consequence of domain swapping, because Cys130 and Cys159 belong to β‐strands C and F, respectively, two disulfide bonds become established between Cys130 in one monomer and Cys159 in the other one. Such a disulfide exchange has already been observed when the nuclear magnetic resonance (NMR) structure of the prion protein was compared to the crystallographic, dimeric one. In both cases, domain swapping implies disulfide exchange because the linker is located in the sequence between two disulfide‐bonded cysteines. As in the CD2 case, the proposed configuration of the CD4 dimer is found as a pair of neighboring monomers in the crystallographic unit cell. Moreover, because in this configuration the epitope of monoclonal antibody MT151, which does not compete with Gp120 for CD4 binding, is in the cleft between the pair of CD4 monomers, it is suggested that MT151 achieves its HIV‐blocking activity by interfering with the formation of CD4 domain‐swapped dimers on cell surface. Proteins 2004. © 2004 Wiley‐Liss, Inc.