Giant cell tumor of tendon sheath (GCTS) and pigmented villonodular synovitis (PVNS) are common synovial "tumors." Their immunohistochemical profile, however, has not been well characterized, and uncertainty exists regarding their histogenesis and relationship to fibroma of tendon sheath. In an effort to clarify these uncertainties and to better define the immunohistochemical profile of GCTS/PVNS, we examined formalin fixed tissue from 35 specimens of GCTS, 12 specimens of PVNS, and three cases of reactive synovitis using avidin biotin complex (ABC) and streptavidin immunohistochemical methods. Antibodies to vimentin, CD68, HAM56, cytokeratins, EMA, S100, HMB45, leukocyte common antigen, CD34, desmin, and smooth muscle actin were used in the study. The proliferating mononuclear cells and surface synovial cells in GCTS/PVNS and reactive synovitis stained positively for CD68, HAM56, and vimentin only. Multinucleated cells stained for CD68, vimentin, and leukocyte common antigen. All other stains were negative. Our results suggest that GCTS/PVNS are tumors of synovial cell origin, and do not support an association between GCTS and fibroma of tendon sheath.