Langerhans cells (LCs) have been identified in human skin by 10 weeks estimated gestational age (EGA), but it was not known when they first enter the epidermis or acquire HLA-DR, OKT-6, and ATPase reactivity. We assayed for LCs in human embryonic and fetal skin by using immunolabeling and histochemical techniques on epidermal sheets. HLA-DR+ and ATPase+ LCs were present in the epidermis by 6-7 weeks EGA, the youngest tissue examined. Most LCs were OKT-6- until about 12 weeks EGA when they underwent a dramatic increase in OKT-6 reactivity. Although LC densities between 50-100 days were statistically similar (100 cells/mm2 of epidermis), LCs early in development were smaller, less dendritic, and phenotypically heterogeneous. We conclude that LCs migrate into the epidermis during the first trimester and resemble the adult phenotype by the second trimester, long before the immune system is fully activated.