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OBJECTIVES: Giant cells are commonly present in inflamed synovium, often in close association with the intimal layer. The nature of these multinucleate cells has been reassessed using new cytochemical and immunochemical techniques. METHODS: Cryostat sections of non-inflamed, rheumatoid arthritic and osteoarthritic synovia were analysed for the presence of CD68 and non-specific esterase, markers associated with macrophages; activity of uridine diphosphoglucose dehydrogenase, associated with fibroblast-like synoviocytes; and tartrate resistant acid phosphatase and the vitronectin receptor subunit CD51, associated with osteoclasts. RESULTS: Giant cells were not seen in non-inflamed tissue. In diseased tissue giant cells in the intimal layer fell into two major groups: CD68 negative or dull cells with high uridine diphosphoglucose dehydrogenase (UDPGD) activity suggestive of true synoviocyte polykaryons; and CD68 positive cells with low UDPGD activity suggestive of macrophage polykaryons. The two groups were seen in samples from patients with rheumatoid arthritis (RA) and patients with osteoarthritis (OA), but the former were more prominent in OA and the latter in RA. Most CD68 positive giant cells also showed tartrate resistant acid phosphatase activity and prominent expression of CD51. As such they were histochemically indistinguishable from osteoclasts, but their bone resorbing capacity remains unknown. CONCLUSIONS: Giant cells in arthritic synovium appear to be of two types, one related to true synoviocytes and one to macrophages.