Human dermatitis-involving cytotoxic interaction between effector lymphocytes and epithelial target cells has thus far been documented in vivo only as naturally occurring disease or as an iatrogenic complication of organ engraftment. In this report, we reproduce human cytotoxic dermatitis via local microinjection of heterologous human lymphocytes into human skin xenografted to mice with severe combined immune deficiency syndrome. Injection sites develop progressive T cell epidermotropism culminating in cytotoxic dermatitis resembling human lichen planus within 4 weeks. Effector T cells express a CD8+, TIA-1+ phenotype, proliferate locally, express interleukin-2 surface receptors, and demonstrate interferon-gamma mRNA induction after microinjection. Migration of these T cells into the epidermis is closely linked to experimental induction and coincident expression of intercellular adhesion molecule by keratinocytes. T cell apposition to keratinocytes is associated with endonuclease-mediated DNA fragmentation (apoptosis) in the latter cell type. Intraepidermal T cell migration and related lesion formation is partially abrogated by systemic administration of antisense oligonucleotide to ICAM-1 mRNA. These findings demonstrate that human cytotoxic tissue injury directed against epithelial targets can be produced and modulated in chimeric mice.