Tissue lesions from eight patients with recurrent oral ulcers (ROU) were subjected to detailed immunohistopathologic studies. In five patients, a specimen of an unaffected area from the opposite site was obtained. The main inflammatory cells in situ were CD3 positive T lymphocytes, with CD4 cells forming approximately half (range 30-60%) and CD8 cells 20% (range 10-30%) of all cells. CD19 positive B lymphocytes formed 5-12% of all cells. Furthermore, 45% (range 15-65%) of all lymphoid cells had signs of previous antigenous contact and had helper/inducer CDw29 type. Suppressor/inducer CD45R cells formed only about 20% (range 7-50%) of all cells. Although this observation suggests involvement of antigen as a causative and/or triggering stimulus, elements of a non-specific inflammatory response were observed as well. Endogenous peroxidase-positive neutrophils were present at the ulcer site, and were occasionally observed intravascularly and in the extracellular matrix in areas characterized by inflammatory mononuclear cell infiltrates. Although the proportion of endogenous peroxidase-positive, recently recruited monocytes was low, CD11b and nonspecific esterase-positive mature tissue macrophages formed about 14% (range 5-35%) of all inflammatory cells in situ, particularly at the periphery of the lymphoid cell infiltrates. Mast cells were also observed in all samples studied, forming 2-5% of inflammatory cells in the richly vascularized connective tissue beneath the basement membrane. In the specimens from clinically unaffected areas, inflammatory cells were rare. Our observations stress the multifaceted nature and participation of multiple effector systems in the local tissue pathogenesis of ROU.