Lichen planus (LP) is a chronic inflammatory disorder involving cutaneous and mucosal surfaces, characterized by a T-cell-mediated immune response against epithelial cells, with persistent accumulation of T lymphocytes and epithelial cell damage. The mechanisms involved in this chronic inflammatory disease are largely unknown. A pivotal role in the pathogenesis of long-lasting inflammatory processes is played by the activation of nuclear factor kappa B (NF-kappaB), a primary transcription factor which upon translocation to the nucleus, binds to promoter regions of different genes encoding immune and pro-inflammatory mediators. Using immunohistochemistry, the present study analysed the expression of NF-kappaB in 25 cases of cutaneous LP (CLP) and 28 cases of oral LP (OLP) and correlated this with the recruitment of cytotoxic T-cells (expressing Tia-1 or perforin) in the inflammatory infiltrate. Nuclear NF-kappaB was expressed on basal and suprabasal keratinocytes in all cases of LP, while normal epithelium was consistently negative; OLP contained significantly higher numbers of NF-kappaB-positive keratinocytes than CLP (means: 89.32 versus 22.6; p<0.05). Furthermore, nuclear NF-kappaB expression by epithelial cells correlated with the amount of cytotoxic cell infiltration (p<0.02). These data suggest that increased NF-kappaB activity may represent the basis of maintenance of the inflammatory response. The differences observed between NF-kappaB expression on epithelial cells in OLP and CLP and their correlation with the degree of cytotoxic inflammatory infiltrate might explain the different clinical courses of the two variants of the disease, since OLP is typically more recalcitrant than CLP. As proposed for other chronic inflammatory disorders associated with increased NF-kappaB activity, the involvement of NF-kappaB in the pathogenesis of LP could be considered for selective therapeutic inhibitory targeting.