We employed a rat model of complete major histocompatibility complex-mismatched allogeneic bone marrow transplantation to better characterize the histologic expression of the acute cutaneous graft-versus-host reaction (GVHR), compared with changes due to the preparative regimen. Cyclosporin A abolished the development of this GVHR. Low levels of dyskeratotic cells were present in all groups (allogeneic and syngeneic transplants with and without cyclosporin A) and, alone, were insufficient to diagnose a cutaneous GVHR. A consistent histologic feature of the GVHR was significant lymphoid infiltration of the dermis. The pattern of cytotoxic folliculitis involved follicular epithelium above the entry of sebaceous glands. Immunostain for major histocompatibility complex class II, IA, and IE antigens revealed that dendritic cells within the follicle were limited to this upper region and that lower follicular epithelium did not upregulate expression with evolution of the GVHR. Based on this model, we conclude 1) that the diagnostic scheme for the acute cutaneous GVHR should include lymphoid infiltration of the dermis, 2) that the preparative regimen (including total body irradiation) induces persistent low levels of dyskeratotic cells (two to three cells/linear mm of epidermis), and 3) that the pattern of follicular involvement may relate to the distribution of dendritic cells and to an inability of lower follicular epithelium to upregulate major histocompatibility complex class II antigens.