The present study investigated the potential involvement of interferon-γ (IFN-γ)-producing cells in the pathogenesis of oral lichen planus (OLP). On biopsies from 10 OLP patients, an in situ hybridization technique was employed to determine the topographical distribution of cells expressing IFN-γ mRNA. It was estimated that approximately 1% or fewer lesional cells were IFN-γ mRNA-positive. These cells were mainly encountered lining the basal membrane in a majority of the patients, or were in a few cases circumscribing the infiltrate, but were more seldom localized to the center of the lesion. A slightly higher, but not statistically significant, number of phytohemagglutinin (PHA)-induced IFN-γ-producing cells, in vitro, was found in blood from 11 other OLP patients compared with blood from matched controls. Equal concentrations of IFN-γ in supernatants from PHA-stimulated blood cells were detected in the two groups. Similarly, the IFN-γ response towards C. albicans was alike in OLP and in healthy control (HC) blood cells, indicating normal immunological memory function in the OLP patients. A small set of cells with spontaneous IFN-γ production was found in OLP and in HC peripheral blood. The data suggest that T-lymphocyte activation and cytokine production act locally and are not reflected in peripheral blood. The localization of the IFN-γ mRNA-positive cells indicates that the antigenic peptides are presented at the periphery of the mononuclear cell infiltrate. Furthermore, the low frequency of IFN-γ mRNA-positive cells in the lesions suggests that the disease is maintained by a small number of antigen-specific T cells.