Inflammatory cells in amalgam-associated, oral lichenoid contact lesions (OLL) were studied in 19 patients by immunocytochemistry using monoclonal antibodies. Ten of the patients displayed allergic patch test (PT) reactions to several mercury compounds and nine were negative. The immunocytochemical quantification showed a uniform composition of the inflammatory mononuclear cells in the two study groups. The number of HLA-D/DR-positive dendritic cells (P<0.001) and CD1a-positive Langerhans cells (P=0.035) was significantly lower in the PT-negative than PT-positive patients. HLA-D/DR expression on keratinocytes varied from negative to full thickness staining of the epithelium. HLA-D/DR expression in the full thickness of epithelium (3) or through the basal and spinous cell layers (2) was seen in 5 of 8 PT-positive patients, whereas none of the PT-negative patients had this staining pattern (P=0.045). These patients also showed a good clinical response after amalgam removal. Consequently, OLL may represent a true delayed hypersensitivity reaction with a trans-epithelial route of entrance of the metal haptens released from dental restorative materials.