Transmission of HIV-1 is predominantly restricted to macrophage (MΦ)-tropic strains. Langerhans ceils (LCs) in mucosal epithelium, as well as macrophages located in the submucosal tissues, may be initial targets for HIV-1. This study was designed to determine whether restricted transmission of HIV-1 correlates with expression and function of HIV-1 co-receptors on LCs and macrophages. Using polyclonal rabbit IgCs specific for the HIV co-receptors cytokines CXCR4 and CCR5, we found that freshly isolated epidermal LCs (resembling resident mucosal LCs) expressed CCR5, but not CXCR, on their surfaces. In concordance with surface expression, fresh LCs fused with Mφ -tropic but not with T-tropic HIV-1 envelopes. However, fresh LCs did contain intracellular CXCR4 protein that was transported to the surface during in vitro culture. Macrophages expressed high levels of both co-receptors on their surfaces, but only CCR5 was functional in a fusion assay. These data provide several possible explanations for the selective transmission of Mφ-tropic HIV variants and for the resistance to infection conferred by the CCR5 deletion.