The expression of TNF-α and its receptors in the rheumatoid synovial membrane was investigated using immunohistochemistry and immunocytofluorescence. TNF-α+ cells (< 10% of all cells) were found in all regions, predominantly in sublining and diffuse infiltrates. The highest percentage of TNF-R+ cells was found in the lining layer (50–90%), with a slight predominance of TNF-R55. In the sublining, fewer cells expressed TNF-R (≈ 50%), mostly TNF-R75. TNF-R75+ cells were also detectable in diffuse infiltrates and lymphoid aggregates (10–50%). These contained only individual TNF-R55+ cells. In diffuse infiltrates, there were slightly more TNF-R55+ cells than in lymphoid aggregates (in both cases < 10%). In sequential sections, TNF-α+ cells localized mostly in the vicinity of TNF-R+ cells. Macrophage-like cells appeared to be the predominant TNF-R+ cell type. CD3+ T cells in lymphoid aggregates expressed exclusively TNF-R75. Subsequently, the expression of membrane-bound TNF-α, TNF-R55 and TNF-R75 was tested by FACS analysis in isolated RA synoviocytes (n = 7 patients). Only four specimens expressed mTNF-α, and that on a low percentage of cells (2 ± 2.4%; mean ± SD). In contrast, all specimens expressed higher percentages of TNF-R55 and TNF-R75 (21 ± 1% and 14 ± 7.1%, respectively). These results demonstrate that: (1) the percentage of cells expressing soluble/transmembrane TNF-α is greatly outnumbered by the percentage of cells expressing TNF receptors; and (2) TNF-α-expressing cells are localized in regions expressing substantial levels of TNF receptors. Therefore, the known pro-inflammatory and pro-arthritic effects of TNF-α are probably mediated by local interactions between the receptors and their soluble and transmembrane ligands.