Objective. To determine the distribution of mast cell subsets and their density in synovium from normal subjects and from patients with osteoarthritis (OA) and rheumatoid arthritis (RA). Methods. A sequential double-immunohistochemical staining technique was used to distinguish mast cells as positive for tryptase only (MG(T)) or for tryptase plus chymase (MC(TC)). Synovial tissue was obtained from RA patients (n = 16), OA patients (n = 18), and normal subjects (n = 15). Sections were analyzed to a depth of 1 mm from the synoviocyte lining layer by quantitative histomorphometry. Immunohistochemical data were correlated with histologic findings and clinical indices of disease activity. Results. In normal synovium, the majority of mast cells belonged to the MC(TC) subset, outnumbering MC(T) cells by 5:1. The mean density of mast cells was significantly increased in RA synovia (60.9 cells/mm2) compared with OA (21.7 cells/mm2) and with normal (9.4 cells/mm2) synovia. Selective expansion of the MC(T) subset accounted for the increased mast cell density in OA. In RA, both subsets expanded and were associated with infiltrating inflammatory cells or with regions of highly cellular fibrous tissue (mainly MC(TC)). An association was noted between clinical parameters of activity or progression of rheumatoid disease and the density of MC(TC) cells, especially the density in the superficial layer of synovium. In RA synovia, we found no evidence of the chymase only, or MC(C), immunophenotype. Conclusion. MC(TC) mast cells expand in RA but not OA, associate with regions of 'active' fibrosis, and correlate with parameters of disease activity or progression of RA. These findings implicate the MC(TC) subset of mast cells in the pathologic mechanisms that mediate tissue damage in RA.