We compared the survival of cultured epithelial allografts and epithelial autografts applied to donor sites for split-thickness skin grafts. Before grafting, cultured epithelium was devoid of Langerhans cells (LCs) or lymphoid cells by immunohistochemical and electron microscopic examinations. The autografts attached to the wounds permanently, without any clinical evidence of rejection. In contrast, allografts, which were mismatched for MHC and blood-type antigens, appeared to adhere firmly only until day 7. By the second week, signs of graft rejection were apparent: The graft changed color, and the underlying dermis underwent "microerosion" and denudation. By the third week, the area formerly occupied by the allograft had the same coloration as ungrafted wounds and apparently had undergone reepithelialization by the host. Immunohistochemical and ultrastructural studies clearly demonstrated that host Langerhans-like cells (without Birbeck granules) appeared in both autografts and allografts. However, these cells were numerous and distributed widely throughout allografts, whereas they were scarce and confined to the basal layer of autografts. Typical Langerhans cells (containing Birbeck granules) were present in the prickle-cell layer of autografts by day 7. The present study strongly indicates that allografts of cultured epithelium are rejected. Furthermore, given the known ability of Langerhans-like cells to function as accessory cells in T-cell activation, our results point to a role for host Langerhans-like cells in immunologically mediated rejection of the epithelial allografts.